Statistical issues and challenges in immuno-oncology

Background: The development of immuno-oncologic agents poses unique challenges, namely that both efficacy and safety profiles differ from previously characterized cytotoxic and pathway-specific agents. In addition, exponential distribution is usually assumed in study designs with time-to-event endpoints such as overall survival or progression-free survival. This assumption might lead to wrong estimates of study duration and statistical power if the phenomena of long term survival and delayed clinical effects are present. The aim here was to evaluate the magnitude of the impact caused by the violation of this assumption, and to describe new ways of analyzing efficacy and safety of immuno-oncologic agents. Methods: Monte Carlo simulation was implemented to explore the impact of long term survivors and delayed treatment effect on study power and trial duration. Scenarios with various combinations of long term and delayed treatment effects were considered. Study power and duration were evaluated based on 10000 randomly generated trial data sets. The utility of group sequential study designs was discussed. A new set of immune-related response criteria (irRC) was considered for efficacy analysis. Two new methods for identifying adverse events, termed immune-related adverse events (irAE) and immune-mediated adverse reactions (imAR) were described. The key features of the safety profiles derived using these two methods were similar. Both methods were aimed at identifying inflammatory adverse events caused by immunotherapies. Results: The presence of long term survivors usually lengthened the study duration. Depending on the treatment effect post survival curve separation, delayed clinical effect in general led to a loss of power. The irRC offered a new way of identifying clinical responses. Both safety analyses demonstrated higher sensitivity of identifying adverse events of immune system origin. Conclusion: This simulation study showed the importance of accounting for the delayed treatment effect and long term survivors when these phenomena were expected. Interim analyses for the purpose of stopping the study for either positive or futile outcome should be implemented with caution in immuno-oncology trials. The new efficacy analysis offered a potential new way of assessing signs of activity in immunotherapies. While the irAE method facilitated prompt and effective management of adverse events, the imAR method captured truly immune-related events

Differential effects of dosing regimen on the safety and efficacy of dasatinib: retrospective exposure-response analysis of a Phase III study.

PurposeDasatinib is a prototypic short half-life BCR-ABL1 tyrosine kinase inhibitor. The recommended dose of dasatinib for chronic myeloid leukemia in chronic phase was changed from 70 mg twice daily to 100 mg once daily following a Phase III dose-optimization study. To better understand the superior benefit-risk profile of dasatinib 100 mg once daily, exposure-response was characterized for efficacy (major cytogenetic response) and safety (pleural effusion).Patients and methodsDasatinib exposure in patients with chronic myeloid leukemia in chronic phase was determined by population pharmacokinetic analysis of data from seven dasatinib clinical studies (N = 981), including the Phase III dose-optimization study (n = 567). Data from the Phase III study were then used to characterize exposure-response relationships for the four dasatinib treatment regimens investigated (100 mg once daily, 50 mg twice daily, 140 mg once daily, and 70 mg twice daily).ResultsMajor cytogenetic response was significantly (P < 0.01) associated with weighted average steady-state dasatinib plasma concentrations, and pleural effusion was significantly associated with trough concentration. Major cytogenetic response was also significantly associated with maintenance of uninterrupted dosing. The 100 mg once daily arm had the lowest steady-state trough concentration of the four dose arms investigated in the Phase III study, and although this arm also had the lowest weighted average steady-state dasatinib plasma concentration, it had the highest dose maintenance.ConclusionDasatinib dose optimization to 100 mg once daily from 70 mg twice daily significantly minimizes adverse events while maintaining efficacy by exploiting differences in the measures of exposure associated with efficacy and safety

Changes in plasma C1q, apelin and adropin concentrations in older adults after descending and ascending stair walking intervention

This study compared changes in plasma complement component 1q (C1q), apelin and adropin concentrations in older obese women after descending (DSW) and ascending stair walking (ASW) training (n = 15/group) performed twice a week for 12 weeks, with gradual increases in exercise time from 5 to 60 min. Fasting blood samples were collected 3 days before the first and 4 days after the last training session. The improvements in the maximal voluntary isometric contraction (MVIC) strength of the knee extensors, functional physical fitness [e.g., 30-s chair stand (CS) performance], resting systolic blood pressure (SBP), insulin sensitivity [e.g., oral glucose tolerance test (OGTT)] and blood lipid profiles [e.g., total cholesterol (TC)] were greater (p \u3c 0.05) in the DSW than ASW group. Plasma C1q decreased (− 51 ± 30%), and apelin (23 ± 15%) and adropin (127 ± 106%) increased (p ≤ .0.05) only after DSW. Significant (p ≤ 0.01) partial correlations were found between the pre- to post-DSW changes in C1q, apelin or adropin and changes in outcome measures [e.g., C1q and MVIC (r = − 0.837), apelin and SBP (r = − 0.854), and andropin and OGTT (r = − 0.729)]. These results showed that greater decreases in plasma C1q and greater increases in apelin and adropin concentrations were associated with greater improvements in outcome measures after DSW than after ASW

Basket trials in oncology: a systematic review of practices and methods, comparative analysis of innovative methods, and an appraisal of a missed opportunity

BackgroundBasket trials are increasingly used in oncology drug development for early signal detection, accelerated tumor-agnostic approvals, and prioritization of promising tumor types in selected patients with the same mutation or biomarker. Participants are grouped into so-called baskets according to tumor type, allowing investigators to identify tumors with promising responses to treatment for further study. However, it remains a question as to whether and how much the adoption of basket trial designs in oncology have translated into patient benefits, increased pace and scale of clinical development, and de-risking of downstream confirmatory trials.MethodsInnovation in basket trial design and analysis includes methods that borrow information across tumor types to increase the quality of statistical inference within each tumor type. We build on the existing systematic reviews of basket trials in oncology to discuss the current practices and landscape. We conceptually illustrate recent innovative methods for basket trials, with application to actual data from recently completed basket trials. We explore and discuss the extent to which innovative basket trials can be used to de-risk future trials through their ability to aid prioritization of promising tumor types for subsequent clinical development.ResultsWe found increasing adoption of basket trial design in oncology, but largely in the design of single-arm phase II trials with a very low adoption of innovative statistical methods. Furthermore, the current practice of basket trial design, which does not consider its impact on the clinical development plan, may lead to a missed opportunity in improving the probability of success of a future trial. Gating phase II with a phase Ib basket trial reduced the size of phase II trials, and losses in the probability of success as a result of not using innovative methods may not be recoverable by running a larger phase II trial.ConclusionInnovative basket trial methods can reduce the size of early phase clinical trials, with sustained improvement in the probability of success of the clinical development plan. We need to do more as a community to improve the adoption of these methods

Comparison of coplanar and noncoplanar intensity-modulated radiation therapy and helical tomotherapy for hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>To compare the differences in dose-volume data among coplanar intensity modulated radiotherapy (IMRT), noncoplanar IMRT, and helical tomotherapy (HT) among patients with hepatocellular carcinoma (HCC) and portal vein thrombosis (PVT).</p> <p>Methods</p> <p>Nine patients with unresectable HCC and PVT underwent step and shoot coplanar IMRT with intent to deliver 46 - 54 Gy to the tumor and portal vein. The volume of liver received 30Gy was set to keep less than 30% of whole normal liver (V30 < 30%). The mean dose to at least one side of kidney was kept below 23 Gy, and 50 Gy as for stomach. The maximum dose was kept below 47 Gy for spinal cord. Several parameters including mean hepatic dose, percent volume of normal liver with radiation dose at X Gy (Vx), uniformity index, conformal index, and doses to organs at risk were evaluated from the dose-volume histogram.</p> <p>Results</p> <p>HT provided better uniformity for the planning-target volume dose coverage than both IMRT techniques. The noncoplanar IMRT technique reduces the V10 to normal liver with a statistically significant level as compared to HT. The constraints for the liver in the V30 for coplanar IMRT vs. noncoplanar IMRT vs. HT could be reconsidered as 21% vs. 17% vs. 17%, respectively. When delivering 50 Gy and 60-66 Gy to the tumor bed, the constraints of mean dose to the normal liver could be less than 20 Gy and 25 Gy, respectively.</p> <p>Conclusion</p> <p>Noncoplanar IMRT and HT are potential techniques of radiation therapy for HCC patients with PVT. Constraints for the liver in IMRT and HT could be stricter than for 3DCRT.</p

Surface Electromagnetic Waves Thermally Excited: Radiative Heat Transfer, Coherence Properties and Casimir Forces Revisited in the Near Field

We review in this article the influence of surface waves on the thermally excited electromagnetic field. We study in particular the field emitted at subwalength distances of material surfaces. After reviewing the main properties of surface waves, we introduce the fluctuation-dissipation theorem that allows to model the fluctuating electromagnetic fields. We then analyse the contribution of these waves in a variety of phenomena. They give a leading contribution to the density of electromagnetic states, they produce both temporal coherence and spatial coherence in the near field of planar thermal sources. They can be used to modify radiative properties of surfaces and to design partially spatially coherent sources. Finally, we discuss the role of surface waves in the radiative heat transfer and the theory of dispersion forces at the subwavelength scale.Comment: Redig\'{e} \`{a} la fin de l'ann\'{e}e 2004. Accept\'{e} dans Surface Science Report

Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma

Background Ipilimumab monotherapy (at a dose of 3 mg per kilogram of body weight), as compared with glycoprotein 100, improved overall survival in a phase 3 study involving patients with previously treated metastatic melanoma. We conducted a phase 3 study of ipilimumab (10 mg per kilogram) plus dacarbazine in patients with previously untreated metastatic melanoma. Methods We randomly assigned 502 patients with previously untreated metastatic melanoma, in a 1:1 ratio, to ipilimumab (10 mg per kilogram) plus dacarbazine (850 mg per square meter of body-surface area) or dacarbazine (850 mg per square meter) plus placebo, given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks through week 22. Patients with stable disease or an objective response and no doselimiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary end point was overall survival. Results Overall survival was significantly longer in the group receiving ipilimumab plus dacarbazine than in the group receiving dacarbazine plus placebo (11.2 months vs. 9.1 months, with higher survival rates in the ipilimumab–dacarbazine group at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%) (hazard ratio for death, 0.72; P<0.001). Grade 3 or 4 adverse events occurred in 56.3% of patients treated with ipilimumab plus dacarbazine, as compared with 27.5% treated with dacarbazine and placebo (P<0.001). No drug-related deaths or gastrointestinal perforations occurred in the ipilimumab–dacarbazine group. Conclusions Ipilimumab (at a dose of 10 mg per kilogram) in combination with dacarbazine, as compared with dacarbazine plus placebo, improved overall survival in patients with previously untreated metastatic melanoma. The types of adverse events were consistent with those seen in prior studies of ipilimumab; however, the rates of elevated liver-function values were higher and the rates of gastrointestinal events were lower than expected on the basis of prior studies. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00324155.

Chronic hepatitis B: whom to treat and for how long? Propositions, challenges, and future directions

Recent guidelines of the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver, and the Asian Pacific Association for the Study of the Liver 2008 update of the “Asian-Pacific consensus statement on the management of chronic hepatitis B” offer comprehensive recommendations for the general management of chronic hepatitis B (CHB). These recommendations highlight preferred approaches to the prevention, diagnosis, and treatment of CHB. Nonetheless, the results of recent studies have led to an improved understanding of the disease and a belief that current recommendations on specific therapeutic considerations, including CHB treatment initiation and cessation criteria, particularly in patient populations with special circumstances, can be improved. Twelve experts from the Asia-Pacific region formed the Asia-Pacific Panel Recommendations for the Optimal Management of Chronic Hepatitis B (APPROACH) Working Group to review, challenge, and assess relevant new data and inform future updates of CHB treatment guidelines. The significance of and controversy about reported findings were discussed and debated in an expert meeting of the Working Group in Beijing, China, in November 2008. This review paper attempts to identify areas requiring improved CHB management and provide suggestions for future guideline updates, with special emphasis on treatment initiation and duration