Clinical Trial Design
A key challenge of clinical trial design for cancer immunotherapeutics is that experience has shown efficacy of therapeutic cancer vaccines “should not be measured” by the standards used for chemotherapeutic agents. Chemotherapy, which directly counteracts tumor growth, can be evaluated on tumor response, or the basis of tumor size. But cancer immunotherapy, experts say, relies on an immune response that may develop only over the course of time.
In some cases, tumors may actually increase in size in the short term. In other cases, the immune response results in prolonged “stable disease,” making overall survival rate a better endpoint than tumor size.
One practical result of this is that patient survival may not be affected until some months after treatment start. For the survival endpoint, Kaplan-Meier curves from randomized immunotherapy trials may show a delayed separation after months, which directly influences the statistical power to determine treatment effects observed over the entire length of the curves.
As a remedy, Hoos and Britten have suggested immunotherapy response criteria derived from RECIST and WHO—immune-related response criteria—be developed. These criteria would capture all clinical activity patterns for a reliable assessment of activity signals in early trials.
Alternative statistical models tailored to address the delayed separation of curves have to consider that all events prior to the separation do not contribute to the differentiation between study arms after the separation, thus leading to loss of statistical power. Such new statistical models need to compensate for this loss of power. They may split the hazard ratio into an early and a late component before and after the separation of curves.
Importantly, the loss of power and absence of early effects should be carefully considered when designing randomized trials with early interim and futility analyses.
This phenomenon has been observed in multiple randomized immunotherapy trials and is often not apparent until 4–8 months or more after random assignment, as in the initial Provenge trial.
Yervoy, an anti-CD4 monoclonal antibody approved in 2011 for treatment of metastatic melanoma, provides an object lesson in the development of novel immunotherapeutics.
The antibody produces durable objective responses and/or stable disease in patients with metastatic melanoma. As more patients were treated with the drug during the course of clinical trials it became clear that “the kinetics of responses are heterogeneous and significantly different from those of chemotherapy and other immunotherapy.”
Though objective response or stable disease were observed within conventional time frames, responses were observed weeks to months after therapy initiation. Response or stable disease may be preceded by apparent early disease progression, or may occur simultaneously with different progressing lesions within the same patient (a “mixed” response).
According to Jedd Wolchok, director of immunotherapy clinical trials at Memorial Sloan-Kettering Cancer Center, “There are some people who we have treated with ipilimumab whose scans look just as abnormal now as they did five years ago, so it has turned it into a chronic disease.
“It changed the situation from something they were dying from into something they are living with. That really does show you that the immune system can restore an equilibrium between the person and the tumor.”
As the NCI announced that the first clinical trials will be launched under its Cancer Immunotherapy Trials Network (CITN) including 27 U.S. cancer centers and universities, Dr. Wolchuk, a CITN investigator, noted that the impact of the Provenge and Yervoy approvals was enormous. “For pharmaceutical companies and the industry to see a successful immunotherapy that can be administered in a doctor’s office has really changed the field.”
While multiple complex challenges exist in designing cancer immunotherapy trials, cancer vaccine developers, researchers note, are well advised to use a homogenous patient population, focus on containing minimum residual disease where vaccines seemed most effective, not use endpoints related to tumor shrinkage, and provide sufficient time for a patient response as there are “no perfect surrogate markers” for efficacy. And, they noted, it takes time to see results.
As more successes accrue, investors may lose some of their insecurities related to cancer immunotherapeutics. “In general, institutional investors remain on the sidelines with regard to interest in immunotherapy companies; they are waiting for additional positive outcomes from clinical trials and commercial success with autologous approaches given the Provenge experience,” Becker aptly remarked.