Clinical Trials Of Systemic Therapy Research Articles

BMScope: A scoping review to chart the evolving clinical study landscape in brain and leptomeningeal metastasis.

Recent studies have challenged the notion that patients with brain metastasis (BM) or leptomeningeal metastasis (LM) should be excluded from systemic therapy clinical trials. This scoping study summarises the BM/LM clinical studies published between 2010 and 2023. MEDLINE, CINAHL, CAB Abstracts, PsycINFO, Cochrane Library, HINARI, International Pharmaceutical Abstracts, PubMed, Scopus, Web of Science, and EMBASE electronic databases were searched on 21 June 2021. An updated search was performed on 21 February 2023. Eligible studies should involve investigation of a therapeutic intervention in solid tumour patients with BM and/or LM and a reported patient outcome. Extracted study-level data, included study type, publication date, geographical location, number of BM/LM patients in study, primary tumour type and type of therapeutic intervention. 4921 unique studies were eligible for analysis. The key finding is that BM/LM clinical research is expanding globally, both observational studies and clinical trials. Despite the shift over time towards a higher proportion of systemic therapy trials, the majority still do not include patients with symptomatic disease and lack reporting of BM/LM specific endpoints. Globally, there has been a trend to more international collaboration in BM/LM clinical studies. This analysis of the BM/LM literature charts the evolving landscape of studies involving this previously excluded population. Given the increasing clinical research activity, particularly involving late-stage systemic therapy trials, it is imperative that due consideration is given to the intracranial activity of new investigational agents. Wider adoption of standardised reporting of intracranial-specific endpoints will facilitate evaluation of relative intracranial efficacy.

Comparison of nivolumab and sorafenib for first systemic therapy in patients with hepatocellular carcinoma and Child-Pugh B cirrhosis.

Patients with decompensated cirrhosis are excluded or underrepresented in clinical trials of systemic therapies for hepatocellular carcinoma (HCC) and comparisons of available therapies are lacking. We aimed to compare overall survival for patients with HCC and Child-Pugh B cirrhosis treated with nivolumab or sorafenib as first systemic treatment. We performed a retrospective cohort study in patients with HCC and Child-Pugh B cirrhosis treated at Veterans Affairs medical centers to compare overall survival, adverse events, and reason for discontinuation of therapy between patients treated with nivolumab or sorafenib as first systemic treatment. All statistical tests were 2-sided. Of those meeting inclusion criteria, 431 patients were treated with sorafenib and 79 with nivolumab. Median OS was 4.0months (95% CI 3.5-4.8) in the sorafenib cohort and 5.0months (95% CI 3.3-6.8) in the nivolumab cohort. In the multivariable Cox proportional hazards model, nivolumab was associated with a significantly reduced hazard of death compared to sorafenib (HR 0.69; 95% CI 0.52-0.91; p=0.008). In a secondary analysis using propensity score methods, results did not reach statistical significance (HR 0.77; 95% CI 0.55-1.06; p=0.11). Treatment was discontinued due to toxicity in 12% of patients receiving nivolumab compared to 36% receiving sorafenib (p=0.001). In patients with HCC and Child-Pugh B cirrhosis, nivolumab treatment may be associated with improved overall survival and improved tolerability compared to sorafenib and should be considered for the first systemic treatment in this population.

Systemic Therapy for Atopic Dermatitis in Older Adults and Adults With Comorbidities: A Scoping Review and International Eczema Council Survey.

BackgroundClinical trials of systemic therapies for atopic dermatitis (AD) often exclude patients based on age and comorbidities.ObjectivesWe conducted a scoping review of observational studies and survey of International Eczema Council (IEC) members on the treatment of AD in patients with liver disease, renal disease, viral hepatitis, HIV, or history of malignancy.MethodsWe searched MEDLINE via Ovid, Embase via Ovid, and Web of Science from inception to September 14, 2020. We mapped the available evidence on the use of cyclosporine, methotrexate, azathioprine, mycophenolate, systemic corticosteroids, and dupilumab for AD in older adults (≥65 years) and adults with the previously mentioned comorbidities. We surveyed IEC members on their preferred systemic medications for each patient population.ResultsWe identified 25 studies on the use of systemic medications in special populations of adults with AD. Although IEC members preferred dupilumab as the first-line systemic agent across all special populations, many could not identify viable third-line systemic therapy options for some populations.ConclusionsData on systemic therapy for AD for older adults and adults with comorbidities are limited. Although IEC members' access to systemic therapies differs geographically, expert opinion suggests that dupilumab is preferred for those patients.

P14.70 BMScope: A systematic mapping review of brain/leptomeningeal metastasis clinical studies from 2010 to 2020

Abstract BACKGROUND Brain metastasis (BM) and leptomeningeal disease (LMD) are typified by a poor prognosis and are an area of unmet clinical need. Historically, patients with central nervous system (CNS) disease have been excluded from systemic therapy clinical trials, particularly with active/leptomeningeal disease. However, increasing prevalence of CNS metastasis is leading to greater interest in BM/LMD. We performed a descriptive analysis of clinical studies investigating BM/LMD management, published between Jan 2010 to Mar 2020. METHODS A comprehensive, customised search strategy was devised for 12 online bibliographic databases, using the following concepts: “clinical study”, “brain metastasis”, “leptomeningeal disease”, “intervention”, “patient-related outcome”. Double screening for inclusion/exclusion was performed on the Rayyan QCRI web application. Published abstracts were also screened for inclusion from ASCO, ESMO, SNO and EANO between 2015–2020. Following full text screening, conflicts were resolved by consensus and data were extracted using an online standardised tool. Data analysis and data visualisation were performed on the R statistical package. RESULTS Overall, 33118 published studies were double screened; 2632 full publications and 628 abstracts were included. Of these, 14.7% reported on unique interventional clinical trials (phase 2 = 267; phase 3 = 80). More than three times the number of clinical trials investigating systemic agents as the sole therapy for BM/LMD were published in Q1 2020 compared to the whole of 2010 (16 vs 5). 42.5% of clinical trials employed a form of local therapy (brain targeted radiotherapy or neurosurgery). Studies reported on patients with BM (n = 2738), LMD (n = 110) or both (n = 119). The majority of studies were performed in North America, Europe or East Asia (88.5% vs 11.5% rest of the world). The top 3 nations involved in published studies were the USA (n = 1155), China (n = 351) and Germany (n = 334). Network analysis demonstrated increasing links between countries. In line with expected BM prevalence, the main tumour sites studied were lung (23.4%), gastrointestinal (17.5%), breast (15%) and melanoma (12.5%). A rising trend of published BM/LMD studies over time was noted, with 83 observational studies/10 clinical trials in 2010 vs. 454 observational studies/80 clinical trials in 2019. CONCLUSION These findings demonstrate that over the last decade there has been a growth in BM/LMD research; likely reflecting an increasing disease prevalence, availability of novel and potentially CNS active agents, as well as more advanced local therapy modalities. BM/LMD clinical research is dominated by a few geographical regions and nations; however, there is an apparent shift to more international collaboration. This comprehensive mapping exercise will enable targeted systematic reviews of the existing evidence base on BM/LMD management.

P-157 Assessing fitness for systemic therapy in hepatocellular carcinoma: Evaluating time on treatment according to Child-Pugh classification, model for end-stage liver disease score, and AFP level

Clinical trials of systemic therapies for hepatocellular carcinoma (HCC) have classically used Child-Pugh classification (CPC) as enrollment criteria to assess severity of hepatic dysfunction related to cirrhosis, and patients outside of CPC A are generally excluded. Information to guide the care of patients with HCC and CPC B and C who might otherwise be candidates for treatment is thus minimal. This is of increased importance as the number of treatment options and effectiveness of these therapies has increased. We sought to further evaluate the impact of pre-treatment characteristics including CPC on the duration of time on that treatment, to take into account both treatment efficacy and tolerability in the setting of underlying cirrhosis. We conducted a retrospective review of medical records from patients with HCC who received systemic therapy at the University of Colorado Cancer Center. Specific therapy and duration of treatment were collected, as well as baseline CPC (A, B, or C), model for end-stage liver disease (MELD) score (<10 / 10-19 / 20-29 and <16/>16), and AFP (<400 / >400) at time of treatment initiation. The mean, median, standard deviation and interquartile range of the duration of treatment were reported for each of these factors, and non-parametric Kruskal-Wallis and Wilcox tests were conducted to compare the duration of treatments according to each. Subgroup analysis was performed by treatment type, defined as immunotherapy and non-immunotherapy, using the same method. The significance level was set to 0.05. Charts from 101 patients with HCC were reviewed. Of these, 90 received systemic therapy, and 86 patients had data sufficient to determine duration of treatment. A total of 5 patients received more than 1 line of systemic therapy, for 91 unique treatment events assessed. Of these, 62% occurred in the first-line setting, 31% in second-line, and 6% in third-line. Treatments were classified as immunotherapy in 55% and non-immunotherapy in 45%. The duration of treatment was significantly different according to the baseline CPC (p = 0.039) by the Kruskal-Wallis test, with CPC C associated with a significantly shorter duration of treatment as compared to CPC A (p = 0.0226). There was not a significant difference in pairwise comparison of CPC A and B. There was also a significant difference in duration of treatment when assessed by MELD score of <16 and >16 (p=0.019), though not according to other MELD cutoffs, nor baseline AFP level or type of treatment. In subset analysis according to treatment type (immunotherapy and non-immunotherapy), there was not a significant difference in duration of treatment according to any of the baseline factors analyzed. In this retrospective assessment, duration of systemic treatment was not significantly different in HCC patients with underlying CPC A and B liver disease, though was shorter in patients with CPC C disease. Baseline MELD score of <16 and >16 was also associated with a longer time on treatment. Further confirmation of this data may help guide treatment consideration for those patients with HCC and liver disease beyond CPC A.

The Outcomes of Systemic Treatment in Recurrent Hepatocellular Carcinomas Following Liver Transplants.

Treatment of hepatocellular carcinoma (HCC) recurrences following liver transplant (LT) is challenging. Most clinical trials of systemic therapies for advanced HCC excluded patients with any history of organ transplant. We aimed to assess the outcomes in using various systemic therapies in patients with post-LT recurrence. Consecutive patients with HCC and recurrences following LT at a large tertiary centre from 2005 to 2018 were reviewed. Overall survival (OS), response rates and adverse events (AEs) were analysed. Forty-three consecutive patients with a recurrence of HCC following LT were identified from 2005 to 2018. Median OS from diagnosis of recurrence was 17months (CI 11.3, 22.7). Early recurrence within 12months of transplant was associated with a significantly worse median survival of 10months (CI 8.5, 11.4) compared to 26months (CI 18.8, 33.2) when recurrences occurred after 12months from transplant (p < 0.001) with a hazard ratio of 0.104 (log-rank test, p < 0.001). A total of 41 patients had received systemic therapies and 79.1% of them were on sorafenib as the first-line treatment. Among these patients treated with sorafenib, median OS from recurrence was 14months (CI 7.3, 20.7). Hand-foot syndrome (34.7%) was most common among AEs followed by diarrhoea (26.7%). Overall, AEs led to dose interruptions in 8.8% of patients. Notably, 47.1% of patients received subsequent lines of systemic therapies after sorafenib. Early recurrence within 1year from transplant was the most significant risk factor. Treatment efficacy and adverse events and tolerability of sorafenib were comparable with those in the setting of advanced HCC without transplant.

Novel agents for atopic dermatitis in patients over 50 years of age: A case series.

Lan et al recently highlighted the under-representation of older adults in clinical trials of systemic therapies for atopic dermatitis (AD). Late-onset AD is increasingly recognized in older adults. Spontaneous remission is uncommon with this phenotype. Existing drug treatments such as corticosteroids, methotrexate, ciclosporin, and azathioprine are complicated by adverse effects including increased malignancy risk, immunosuppression in the context of immunosenescence, and drug interactions in the setting of polypharmacy. A case series is presented of seven patients over 50 years of age with AD who were prescribed dupilumab or tofacitinib or upadacitinib for at least 6 months. All patients were clear or almost clear (investigator global assessment score 0/1) after 1 month of therapy. No significant adverse events were seen. This case series provides preliminary evidence about the safety and efficacy of these novel drugs for AD in older adults. Further studies with higher numbers of participants are needed to obtain real-world evidence for these drugs in older adults, given the limited data in clinical trials.

Association of early recurrence within one year of liver transplant for hepatocellular carcinoma with poor survival.

296 Background: Treatment of hepatocellular carcinoma (HCC) recurrences following liver transplant is challenging. All the clinical trials of systemic therapies for advanced HCC excluded patients with any history of organ transplant. Here we review outcome, and the safety and efficacy of the application of systemic medical therapies in this clinical setting. Methods: This is a retrospective cross-sectional study of consecutive adult patients with recurrence of HCC following liver transplant for the indication of treatment of HCC in Queen Mary Hospital from January 2005 to January 2018. Results: Forty-three consecutive patients with a recurrence of HCC following liver transplant were identified from 2005 to 2018. Median survival from diagnosis of recurrence was 17 months (CI 11.3, 22.7). Early recurrence within 12 months of transplant was associated with a significantly worse median survival of 10 months CI 8.5, 11.4) compared to 26 months (CI 18.8, 33.2) when recurrences occurred after 12 months from transplant (p&lt; 0.001) after adjustment with peritumoural vascular invasion, first line therapy with sorafenib, any second line therapy and use of mTOR inhibitors as immunosuppressants, with a hazard ratio of 0.104 (log-rank test, p&lt;0.001). 41 patients who received medical systemic therapies, 34 (79.1% ) received sorafenib as the first line systemic therapy. 47.1% (N= 16) received subsequent lines of systemic therapies (ranging from 1 to 4 lines). Hand-foot syndrome was most common among the adverse events and it was observed in 34.7% patients treated with sorafenib. It led to dose interruptions in 8.8 % of patients who were given sorafenib. 26.7% had grade 1 diarrhoea. 14.3% had grade 1 transaminase rise. Conclusions: Early recurrence within one year from transplant was the most significant risk factor. Treatment efficacy and adverse events and tolerability of sorafenib were comparable with those in the setting of advanced HCC without transplant.

Comparative Efficacy of Atezolizumab plus Bevacizumab and Other Treatment Options for Patients with Unresectable Hepatocellular Carcinoma: A Network Meta-Analysis

Background: Most phase 3 clinical trials of systemic therapy for first-line unresectable hepatocellular carcinoma (HCC) have failed, with the exception of SHARP, REFLECT, and IMbrave150. We conducted indirect comparisons of therapies evaluated for first-line HCC treatment. Summary: We conducted a systematic review and meta-analysis of treatments for adults with locally advanced or metastatic unresectable HCC and no prior systemic treatment, including atezolizu­mab plus bevacizumab, sorafenib, lenvatinib, nivolumab, selective internal radiotherapy (SIRT), transarterial chemoembolization, and placebo or best supportive care. Randomized controlled trials published from January 1, 2007, to March 12, 2020, were retrieved from MEDLINE and Embase. Qualitative assessment of heterogeneity evaluated study designs, populations, and outcomes. Indirect comparisons used generalized linear models with random effects within a Bayesian framework and informative priors. We calculated relative efficacy estimates with 95% credible intervals (CrIs) and Bayesian posterior probability estimates of atezolizumab-bevacizumab being superior to other treatments. Nine clinical studies with a total of 3,897 participants were identified from 8,783 records and used to build the all-trials evidence network. Indirect comparisons suggested an improved overall survival (OS) with atezolizumab-bevacizumab versus lenvatinib (odds ratio, 0.63 [95% CrI 0.39–1.04]; with 97% Bayesian posterior probability of being superior), nivolumab (0.68 [95% CrI 0.41–1.14]; 94%), sorafenib (0.59 [95% CrI 0.39–0.87]; 99%), SIRT (0.51 [95% CrI 0.32–0.82]; 100%), or placebo/best supportive care (0.40 [95% CrI 0.25–0.64]; 100%). Key Messages: Within the context of indirect comparisons, analyses of OS favored atezolizumab-bevacizumab versus other treatment options for patients with locally advanced or metastatic unresectable HCC.

Progression-Free Survival Early Assessment Is a Robust Surrogate Endpoint of Overall Survival in Immunotherapy Trials of Hepatocellular Carcinoma.

Simple SummarySurrogate radiology-based endpoints such as progression-free survival (PFS) and objective response rate (ORR) are commonly used in oncology. However, their surrogacy with overall survival (OS) has not been evaluated in immunotherapy trials for hepatocellular carcinoma (HCC). We found that the surrogacy of PFS with OS is highly variable depending on treatment class (immune-checkpoint inhibitors or multikinase inhibitors) and evaluation time-point. Early PFS is a robust surrogate endpoint for OS in immunotherapy trials, while the surrogacy relationship between ORR and OS is weak. Early assessment of PFS could be useful for allowing analyses with small sample sizes and short accrual times, enhancing the interpretability of immunotherapy trials in HCC.Background: Radiology-based outcomes, such as progression-free survival (PFS) and objective response rate (ORR), are used as surrogate endpoints in oncology trials. We aimed to assess the surrogacy relationship of PFS with overall survival (OS) in clinical trials of systemic therapies targeting advanced hepatocellular carcinoma (HCC) by novel meta-regression methods. Methods: A search of databases (PubMed, American Society of Clinical Oncology (ASCO), and European Society for Medical Oncology (ESMO) Meeting Libraries, Clinicaltrials.gov) for trials of systemic therapies for advanced HCC reporting both OS and PFS was performed. Individual patient data were extracted from PFS and OS Kaplan–Meier curves. Summary median PFS and OS data were obtained from random-effect model. The surrogate relationships of median PFS, first quartile (Q1), third quartile (Q3), and restricted mean survival time (RMST) for OS were evaluated by the coefficient of determination R2. Heterogeneity was explored by meta-regression. Results: We identified 49 trials, 11 assessing immune-checkpoint inhibitors (ICIs) and 38 multikinase inhibitors (MKIs). Overall, the correlation between median PFS and median OS was weak (R2 = 0.20. 95% Confidence Intervals [CI]-0.02;0.42). Surrogacy robustness varied between treatment classes and PFS endpoints. In ICI trials only, the correlations between Q1-PFS and Q1-OS and between 12-month PFS-RMST and 12-month OS-RMST were high (R2 = 0.89, 95%CI 0.78–0.98, and 0.80, 95% CI 0.63–0.96, respectively). Interaction p-values obtained by meta-regression confirmed the robustness of results. Conclusions: In trials of systemic therapies for advanced HCC, the surrogate relationship of PFS with OS is highly variable depending on treatment class (ICI or MKI) and evaluation time-point. In ICI trials, Q1-PFS and 12-month PFS-RMST are robust surrogate endpoints for OS.

Novel systemic therapy for hepatocellular carcinoma.

Systemic therapy for hepatocellular carcinoma (HCC) used to be limited to patients with advanced diseases and multi-kinase inhibitors targeting tumor angiogenesis the major approach of developing new treatment options. In the past 3years, new data from trials of both molecular targeted therapy and immune checkpoint inhibitors (ICI) provided many new options of first- and second-line treatment for advanced HCC. Most notably, combination of ICI targeting the program cell death-1 (PD-1) pathway with other novel agents or conventional anti-cancer therapy may further improve treatment efficacy in different clinical settings. In thispaper updated data of clinical trials of systemic therapy in the first- and second-line settings for advanced HCC were reviewed and the following issues werediscussed: (1) lessons of trial design learned from positive and negative trials; (2) the balance between efficacy and safety in clinical practice; and (3) impact on future multi-disciplinary management of HCC.

Alliance A071401: Phase II trial of FAK inhibition in meningiomas with somatic NF2 mutations.

2502 Background: Patients with progressive or recurrent meningiomas have limited treatment options. Clinical trials of systemic therapies for meningiomas have failed to demonstrate benefit. FAK inhibition has a synthetic lethal relationship with NF2 loss. Given the predominance of NF2 mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically-driven phase II study in recurrent or progressive grade I-III meningiomas. Methods: Eligible patients (pts) whose tumors screened positively for NF2 mutations were treated with GSK2256098 750mg po bid until progressive disease in 2 separate cohorts: grade I or II/III meningiomas. Two co-primary endpoints were used: progression-free survival at 6 months (PFS6) and response rate (RR) by Macdonald criteria; per study design, the trial would be declared positive if either endpoint was met. RR was evaluated across the overall cohort; PFS6 was evaluated within each subgroup. Historical benchmark data was obtained from Kaley et al. Neuro Oncol 2014. In the grade I group, 12 evaluable pts provided &gt;79% power to detect a PFS6 rate &gt;65% (vs. null hypothesis of 25%; alpha=0.014). In the grade II/III group, 24 evaluable pts provided &gt;85% power to detect a PFS6 &gt;41.5% (vs. null 15%; alpha=0.02). The threshold for promising results for PFS6 was: 7+/12(grade I) and 8+/24(grade II/III) pts. For RR, 36 evaluable pts provided &gt;94% power to detect RR &gt;20% (vs. null 2.5%; alpha= 0.012). Results: Of 322 pts screened for all mutation cohorts of the study, 36 eligible and evaluable pts with NF2 mutations were enrolled. Across all grades, one pt had a partial response and 24 had stable disease as best response to treatment. In Grade I pts, the observed PFS6 rate was 83% (10/12 pts; 95% CI: 52-98%). In Grade II/III pts, the observed PFS6 rate was 33% (8/24 pts; 95% CI: 16-55%). The study met PFS6 efficacy endpoint both for the Grade I and the Grade II/III cohorts. Treatment was well tolerated. Only 7 patients had a maximum grade-3 adverse event that was at least possibly related to treatment; toxicities across these pts included: proteinuria (2), rash (1), pain (1), ALT (1), AST (1), cholecystitis (1), hypertriglyceridemia (1), apraxia (1), and lymphopenia (1) with no grade 4 or 5 events. Conclusions: GSK2256098 had excellent tolerability andresulted in an improved PFS6 rate in pts with recurrent or progressive NF2-mutated meningiomas. Trial endpoint was met. FAK inhibition warrants further evaluation in this patient population. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org Clinical trial information: NCT02523014 .

The Evolution of Clinical Trials in Metastatic Breast Cancer: Design Features and Endpoints That Matter.

The evolution of thought in assessing benefit in clinical trials of systemic therapy for metastatic breast cancer (MBC) is well documented, with most agents garnering regulatory approval based either on an advantage in overall survival (OS), time to progression (TTP), or progression-free survival (PFS) over an existing standard of care or objective response rate (ORR). Previous guidance for industry on clinical trial endpoints for the approval of cancer drugs and biologics was provided by the U.S. Food and Drug Administration (FDA) in 2007 and recently updated in 2018. The more recent FDA guidance recognizes that advances in science are facilitating the development of oncology products, which "may also result in the identification of additional endpoints that may be used to support approval of oncology products." This article critically addressed the evolution of thought on the advancement of clinical trials in MBC, from various stakeholder perspectives. Despite the term "stakeholder," the objective of all co-authors and parties concerned is to promote and inform the optimal design, conduct, and reporting of clinical trials for women with advanced breast cancer toward improving and extending lives. This article provides an overview of the evolving perspectives on this issue from the physician, regulatory agency, and patient and/or advocate points of view.

Placebo responses in randomized controlled trials for systemic therapy in atopic dermatitis: A systematic review and meta-analysis

Atopic dermatitis (AD) has a variable disease course and intermittent triggers, and responses to topical therapy vary, potentially affecting the magnitude of the placebo response in AD trials. To determine the predictors of increased placebo response in randomized controlled trials ofAD. We performed a systematic review and meta-analysis of randomized controlled trials for systemic therapy in AD published during 2007-2018. We searched the Cochrane Library, Medline, Embase, Global Resource for EczemA Trials (GREAT), Literature of the Latin American and Caribbean Health Sciences (LILACS), and Scopus. Two authors performed study selection and data extraction. Multivariable mixed models were constructed for Cohen D of Eczema Area and Severity Index (EASI), SCORing Atopic Dermatitis (SCORAD), numeric rating scale (NRS)-itch and visual analog scale (VAS)-itch, and Dermatology Life Quality Index (DLQI). Overall, 64 trials were included. Use of concomitant topical therapy prescriptions, study duration ≥3months, and fewer treatment arms were associated with an increased placebo response for EASI, NRS- and VAS-itch, and DLQI. For EASI, the placebo response was increased in studies with a higher proportion of male patients, mild-moderate mean baseline EASI scores, and no blinding. For NRS-itch, and VRS-itch, higher placebo responses were associated with higher proportions of male patients and moderate-severe mean itch scores at baseline. Placebo responses can be reduced in clinical trials of systemic therapy in AD by incorporating double- and triple-blinding, balancing the sex distribution of patients, disallowing concomitant use of prescription topical therapy, and having shorter study durations.

Systematic review of placebo responses in randomized clinical trials of systemic therapy for atopic dermatitis

Systematic review of placebo responses in randomized clinical trials of systemic therapy for atopic dermatitis

Phase 3 Assessment of the Automated Bone Scan Index as a Prognostic Imaging Biomarker of Overall Survival in Men With Metastatic Castration-Resistant Prostate Cancer

Prostate cancer commonly metastasizes to bone, and bone metastases are associated with pathologic fractures, pain, and reduced survival. Bone disease is routinely visualized using the technetium Tc 99m (99mTc) bone scan; however, the standard interpretation of bone scan data relies on subjective manual assessment of counting metastatic lesion numbers. There is an unmet need for an objective and fully quantitative assessment of bone scan data. To clinically assess in a prospectively defined analysis plan of a clinical trial the automated Bone Scan Index (aBSI) as an independent prognostic determinant of overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC). This investigation was a prospectively planned analysis of the aBSI in a phase 3 multicenter randomized, double-blind, placebo-controlled clinical trial of tasquinimod (10TASQ10). Men with bone metastatic chemotherapy-naïve CRPC were recruited at 241 sites in 37 countries between March 2011 and August 2015. The statistical analysis plan to clinically evaluate the aBSI was prospectively defined and locked before unmasking of the 10TASQ10 study. The analysis of aBSI was conducted between May 25, 2016, and June 3, 2017. The associations of baseline aBSI with OS, radiographic progression-free survival (rPFS), time to symptomatic progression, and time to opiate use for cancer pain. Of the total 1245 men enrolled, 721 were evaluable for the aBSI. The mean (SD) age (available for 719 men) was 70.6 (8.0) years (age range, 47-90 years). The aBSI population was representative of the total study population based on baseline characteristics. The aBSI (median, 1.07; range, 0-32.60) was significantly associated with OS (hazard ratio [HR], 1.20; 95% CI, 1.14-1.26; P < .001). The median OS by aBSI quartile (lowest to highest) was 34.7, 27.3, 21.7, and 13.3 months, respectively. The discriminative ability of the aBSI (C index, 0.63) in prognosticating OS was significantly higher than that of the manual lesion counting (C index, 0.60) (P = .03). In a multivariable survival model, a higher aBSI remained independently associated with OS (HR, 1.06; 95% CI, 1.01-1.11; P = .03). A higher aBSI was also independently associated with time to symptomatic progression (HR, 1.18; 95% CI, 1.13-1.23; P < .001) and time to opiate use for cancer pain (HR, 1.21; 95% CI, 1.14-1.30; P < .001). To date, this investigation is the largest prospectively analyzed study to validate the aBSI as an independent prognostic imaging biomarker of survival in mCRPC. These data support the prognostic utility of the aBSI as an objective imaging biomarker in the design and eligibility of clinical trials of systemic therapies for patients with mCRPC. ClinicalTrials.gov Identifier: NCT01234311.

Understanding patterns of brain metastasis in breast cancer and designing rational therapeutic strategies.

One of the most feared sequelae after a diagnosis of advanced breast cancer is development of metastases to the brain as this diagnosis can affect physical function, independence, relationships, quality of life, personality, and ultimately one's sense of self. The propensity to develop breast cancer brain metastases (BCBMs) varies by subtype, occurring in up to one half of those with triple negative breast cancer (TNBC), approximately a third of HER+ breast cancers and 14% in hormone positive disease. Median survival after BCBM diagnosis can be as short as 5 months in TNBC and 10-18 months in the other subtypes. Here, we review the biology of BCBMs and how it informs the rational design of new therapeutic approaches and agents. We discuss application of novel targeted and immunotherapies by breast cancer subtype. It is noteworthy that there are no U.S. Food and Drug Administration (FDA)-approved treatments specifically for BCBMs currently. Nevertheless, there are legitimate grounds for hope as patients with BCBMs are now being included in clinical trials of systemic therapies and a better understanding of the biology and genetic underpinning of BCBMs is driving an increased range of options for patients.

A Systematic Review of Health-Related Quality of Life Reporting in Ovarian Cancer Phase III Clinical Trials: Room to Improve.

Epithelial ovarian cancer (OC) remains a significant cause of morbidity and mortality for women worldwide. Patients may experience a multitude of disease- and treatment-related symptoms that can impact quality of life (QOL) and should be measured and reported in clinical trials. This systematic review investigated the adequacy of reporting of QOL in randomized phase III trials in OC in both the first-line and recurrent disease setting. A systematic review of MEDLINE and EMBASE identified randomized clinical trials of systemic therapy in OC from 1980 to 2014. The adequacy of reporting QOL was evaluated with respect to adherence to established guidelines on reporting QOL in clinical trials and the recent recommendations on the inclusion of patient-reported outcomes in clinical trials from the Fifth Ovarian Cancer Consensus Conference. Of 3,247 abstracts, 35 studies, including 24,664 patients, met inclusion criteria. Twenty-two trials (63%) were in the first-line setting, with 13 (37%) in the recurrent setting. The inclusion of QOL assessments increased from 2% (1980s) to 62% (2010+). Quality of life was a co-primary endpoint in only one trial.Minimal clinically important differences in QOL were defined in eight trials (23%), with results included in the abstract in 37% and article in 86%. Compliance was reported in 26 trials (74%), with 13 trials (37%) reporting specifically how they dealt with missing data. Only seven trials reported the reasons for missing data (20%).Group results were published in 29 trials (83%), with 6 (17%) reporting individual patient results. Results were more commonly reported as a mean overall score (21 trials; 60%), with specific domain scores in only 9 trials (26%). No studies reported QOL beyond progression or included predefined context-specific endpoints based on objectives of treatment (i.e., palliation/cure/maintenance) and the patient population. Duration of benefit of palliative chemotherapy was reported in only one study. Inclusion and reporting of QOL as a trial endpoint has improved in phase III trials in OC, but there are still significant shortfalls that need to be addressed in future trials. The impact of treatment on quality of life (QOL) is an important consideration in patients with ovarian cancer for whom treatment is often given with palliative intent. Both the disease and treatment impact a patient's QOL and require careful evaluation in clinical trials. Matching the QOL questions to the patient population of interest is critical. Similar rigor to that used to assess progression-based endpoints is essential to guide clinical decisions. This systematic review demonstrated that although the inclusion and reporting of QOL as a trial endpoint has improved in phase III trials there are still significant shortfalls that need to be addressed in future trials.

Eligibility for phase 3 clinical trials of systemic therapy in real-world patients with metastatic renal cell cancer managed in a rural region.

Previous research has identified disparities between urban and rural cancer care, including clinical trial access. Therefore, we addressed three different questions in patients with metastatic renal cell cancer managed according to national guidelines in a rural Norwegian standard practice setting. (1) How many patients would have been eligible for three recent landmark randomized clinical trials? (2) Is survival different between eligible and non-eligible patients receiving first-line systemic therapy? (3) Is survival different between eligible patients and published trial results? We performed a retrospective analysis of 101 consecutive patients (2006-2016). Only 52% of the patients were eligible for the first-line study of pazopanib versus sunitinib. The main reasons for violating inclusion or exclusion criteria were presence of brain metastases, absence of clear cell histology, and poor performance status. Even fewer patients were eligible for trials of nivolumab and cabozantinib in pre-treated patients. Eligible patients had significantly better survival than non-eligible patients, median 29.2 versus 8.5months (p=0.0001). These results confirm that many patients from rural practices do not fulfill all mandatory trial eligibility criteria. However, eligible patients managed according to national guidelines had survival outcomes in line with published first-line trial results.

Patients with Advanced Non–Small Cell Lung Cancer: Are Research Biopsies a Barrier to Participation in Clinical Trials?

ObjectivesClinical trials of therapies for non–small cell lung cancer (NSCLC) are increasingly requiring mandatory tumor samples or research biopsies, both of which are potential barriers to trial participation. We assessed the impact of performance of research biopsies on the enrollment of patients with advanced NSCLC in clinical trials. MethodsThe cases of patients with advanced NSCLC who had been evaluated for clinical trials of systemic therapy at the Princess Margaret Cancer Centre from January 2007 to March 2015 were reviewed. ResultsOf the 55 clinical trials identified, 38 required tumor samples for enrollment. Six mandated repeat biopsies, whereas 32 permitted use of archival samples. Trial participation was offered to 636 patients at 940 unique study encounters, with some patients enrolling in multiple trials. Of the patients in 549 encounters during which participation in a therapeutic trial was offered, 60% received study treatment. More patients received study treatment (83% versus 55%, p < 0.0001) and study treatment was started earlier (after 9 days versus after 16, p = 0.002) when the trial did not have a mandatory tissue sample requirement. A similar trend was noted for trials permitting use of archival tissue versus mandatory repeat biopsies. The most common barriers to trial enrollment included absence of a required biomarker (34%), withdrawal of consent (20%), deterioration or death (17%), other exclusion criteria (15%), and insufficient biopsy tissue (10%). ConclusionA growing number of NSCLC trials are requiring tumor tissue for treatment eligibility, which appears to be a significant barrier to trial enrollment. Potential solutions include use of available diagnostic samples (e.g., cytology samples), development of peripheral blood assays for molecular markers, faster central laboratory testing turnaround time, and more resources for rapid biopsy.