Using Win Odds to Improve Commit-to-Phase-3 Decision-Making in Oncology.

Making good decisions about whether to commit-to-phase 3 clinical trials is challenging. This is especially true in oncology because the relationships between the registration endpoint, overall survival, and endpoints such as progression-free survival and confirmed objective response are often poorly understood. We present a framework for decision-making based on a three-endpoint win odds.

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

Background: Basket 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.

Impact of COVID-19 pandemic on oncology clinical trial design, data collection and analysis.

Background: To identify and assess via simulation the impact of COVID-19 pandemic on oncology trials and discuss potential mitigation strategies for study design, data collection, endpoints and analyses.

Methods: We simulated clinical trials to evaluate the COVID-19 impact on overall survival and progression-free survival. We evaluated survival in single-region trials with different proportions of impacted patients across treatment arms, and in multi-region randomized trials with different proportions of impacted patients across regions.

Designing Late-Stage Randomized Clinical Trials with Cancer Immunotherapy: Can We Make It Simpler?

The knowledge we have accumulated over the past few years in the field of cancer immunotherapy has prompted the research community to challenge the status quo of trial design and endpoint selection across all drug development phases. For the design of randomized phase III studies using overall survival (OS) as the primary endpoint in particular, the paradigm has shifted from the conventional approach based on a proportional hazards model to those that account for the unique survival kinetics observed in immuno-oncology trials, such as long-term survival and delayed clinical effect. These new approaches usually require complex modeling or simulations, as well as assumptions about the length of delay in clinical effect and the long-term survival rate, making the process of implementing these new designs challenging.

Relapse-Free Survival as a Surrogate for Overall Survival in the Evaluation of Stage II-III Melanoma Adjuvant Therapy.

Background: We assessed whether relapse-free survival (RFS; time until recurrence/death) is a valid surrogate for overall survival (OS) among resected stage II-III melanoma patients through a meta-analysis of randomized controlled trials.

Methods: Individual patient data (IPD) on RFS and OS were collected from 5826 patients enrolled in 11 randomized adjuvant trials comparing interferon (IFN) to observation. In addition, IPD from two studies comparing IFN and vaccination in 989 patients were included.

Predicting analysis times in randomized clinical trials with cancer immunotherapy.

Background: A new class of immuno-oncology agents has recently been shown to induce long-term survival in a proportion of treated patients. This phenomenon poses unique challenges for the prediction of analysis time in event-driven studies. If the phenomenon of long-term survival is not accounted for properly, the accuracy of the prediction based on the existing methods may be substantially compromised.

Statistical Challenges in the Design of Late-Stage Cancer Immunotherapy Studies.

The past several years have witnessed a revival of interest in cancer immunology and immunotherapy owing to striking immunologic and clinical responses to immune-directed anticancer therapies and leading to the selection of "Cancer Immunotherapy" as the 2013 Breakthrough of the Year by Science. But statistical challenges exist at all phases of clinical development. In phase III trials of immunotherapies, survival curves have been shown to demonstrate delayed clinical effects, as well as long-term survival.

Milestone Survival: A Potential Intermediate Endpoint for Immune Checkpoint Inhibitors.

Recent advancements in cancer immunotherapies offer diverse strategies for cancer treatment. Among the most promising approaches is the blockade of immune checkpoint molecules to activate antitumor immunity. With targeted immunotherapies of new mechanisms of action come greater challenges in study design and statistical analysis, as well as the need for refining clinical trial endpoints.

Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial.

Purpose: There is evidence from nonrandomized studies that a proportion of ipilimumab-treated patients with advanced melanoma experience long-term survival. To demonstrate a long-term survival benefit with ipilimumab, we evaluated the 5-year survival rates of patients treated in a randomized, controlled phase III trial.

Patients And Methods: A milestone survival analysis was conducted to capture the 5-year survival rate of treatment-naive patients with advanced melanoma who received ipilimumab in a phase III trial.

Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma.

Purpose: To provide a more precise estimate of long-term survival observed for ipilimumab-treated patients with advanced melanoma, we performed a pooled analysis of overall survival (OS) data from multiple studies.

Methods: The primary analysis pooled OS data for 1,861 patients from 10 prospective and two retrospective studies of ipilimumab, including two phase III trials. Patients were previously treated (n = 1,257) or treatment naive (n = 604), and the majority of patients received ipilimumab 3 mg/kg (n = 965) or 10 mg/kg (n = 706).

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

Purpose: Dasatinib 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).

Exposure-response relationships of the efficacy and safety of ipilimumab in patients with advanced melanoma.

Purpose: This retrospective analysis was conducted to characterize ipilimumab exposure-response relationships for measures of efficacy and safety in patients with advanced melanoma.

Experimental Design: Data were pooled from 498 patients who received ipilimumab monotherapy at 0.3, 3, or 10 mg/kg in 1 of 4 completed phase II clinical trials.

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.

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.

Ipilimumab efficacy and safety in patients with advanced melanoma: a retrospective analysis of HLA subtype from four trials.

Ipilimumab is a fully human, monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 to potentiate an antitumor T-cell response. This agent improved overall survival in a phase III trial in previously treated patients with advanced melanoma. Because the mechanism of action for ipilimumab is thought to be HLA independent, most trials enrolled patients without regard to HLA subtype.

Dasatinib early intervention after cytogenetic or hematologic resistance to imatinib in patients with chronic myeloid leukemia.

Background: Although many patients with chronic myeloid leukemia (CML) respond well to imatinib therapy, a significant proportion loses their initial response. Loss of response on imatinib is often because of BCR-ABL mutations. Dasatinib is a 325-fold more potent inhibitor of Bcr-Abl than imatinib and has been associated with high rates of durable responses in patients with CML in chronic phase (CP) after imatinib failure.

Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias.

Background: The BCR-ABL tyrosine kinase inhibitor imatinib is effective in Philadelphia chromosome-positive (Ph-positive) leukemias, but relapse occurs, mainly as a result of the outgrowth of leukemic subclones with imatinib-resistant BCR-ABL mutations. We evaluated dasatinib, a BCR-ABL inhibitor that targets most imatinib-resistant BCR-ABL mutations, in patients with chronic myelogenous leukemia (CML) or Ph-positive acute lymphoblastic leukemia (ALL).

Methods: Patients with various phases of CML or with Ph-positive ALL who could not tolerate or were resistant to imatinib were enrolled in a phase 1 dose-escalation study.

Nonparametric prediction of event times in randomized clinical trials.

In clinical trials with planned interim analysis, it can be valuable for logistical reasons to predict the times of landmark events such as the 50th and 100th event. Bagiella and Heitjan (Stat Med 2001; 20: 2055-63) proposed a parametric prediction model for failure-time outcomes assuming exponential survival and Poisson enrollment. When little is known about the distributions of interest, there is concern that parametric prediction methods may be biased and inefficient if their underlying distributional assumptions are invalid.