A report in the November 1, 2015, issue of the Journal of Clinical Oncology, “Pseudoprogression and Immune-Related Response in Solid Tumors,” raised important questions about measuring the efficacy of immunotherapy in the treatment of cancer. Immuno-oncology has become a major field of research, and scientists are applying immunotherapy to the treatment of many cancers. However, certain factors, including immune-related patterns of observed responses and pseudoprogression, make measuring clinical efficacy especially challenging.
fThe article’s authors note that treatment efficacy is typically judged by guidelines created by the World Health Organization (WHO) and the Response Evaluation Criteria in Solid Tumors (RECIST) Group. While these criteria are not perfect, they have guided years of drug approvals for use in cancer treatment and physician decisions about tumor response to such treatments.
One of the biggest issues with the RECIST criteria is pseudoprogression, which involves the temporary increase of tumor size, sometimes accompanied by the development of new lesions. Pseudoprogression may be diagnosed as progressive disease in a premature manner according to WHO and RECIST guidelines. These well-documented issues spurred the development of immune-related response criteria in 2009. These new criteria have since served as the basis for judging efficacy of immunotherapeutic treatments.
The article argues that these criteria need to be revised to reflect better characterization of immune-related responses. Immune responses can prove very subtle and too little data on immune response dynamics data is available for consistent efficacy judgments. Because of this, there is the possibility of overtreating patients with immunotherapies that could be causing harm without providing any real benefit.
Issues with the Immune-Response Criteria
One of the best examples of the issues arising out of current criteria arose during trials of Keytruda, an immuno-oncology agent manufactured by Merck to treat melanoma. The study found that 12 percent of more than 400 patients involved responded to treatment or had stable disease according to the immune-response criteria. However, RECIST criteria would have classified these same patients as having progressive disease.
Keytruda was one of the earliest drugs to enter clinical trial stages, but large numbers of immunotherapy agents now undergoing clinical trials give a better picture of what pseudoprogression looks like, especially in solid tumors. Many of the trials currently in progress are looking at PD-1 and PD-L1 inhibitors in solid tumors. Unfortunately, many of the studies are not using immune-response criteria, which can make direct comparison difficult. The studies primarily use RECIST 1.0 and RECIST 1.1, as well as modified WHO criteria to judge progression, but the majority also rely on investigator-determined immune-response criteria, which can make judgment more subjective.
Less than a third of studies examined made the effort to compare RECIST criteria to immune-related response criteria in a manner that allows direct comparison. Moving forward, more direct comparison would offer invaluable data about the role that pseudoprogression plays in judging clinical benefit. It would also help map out the dynamics of immune response to tumors in the presence of immunotherapy.
The Potential Impact of Efficacy Information
As the authors of the article point out, greater understanding of treatment efficacy can have a major impact on the field of palliative care. Currently, very little information exists about immunotherapy in this area, but as these treatments begin to be affirmed as life-extending therapies, this link will become necessary. Immune-based approaches tend to have rapid and even dramatic responses in some patients, which has increased interest among patients facing the end of life. The challenge that immuno-oncology could introduce to palliative care is balancing the quality-of-life needs of the majority with the potential for long-term responses in a subset of patients.
A patient that has progressed according to RECIST criteria could still benefit from immunotherapy, but at what point do physicians draw the line between delayed response and prolongation of treatment that is not working. In other words, waiting for a response from immunotherapies could delay the transition to other lines of therapy and could minimize the effects of other supportive medications, such as steroids.
If patients with metastatic cancer now have a chance at a durable response, it makes sense to try immunotherapies, but it is necessary to have clear criteria for judging efficacy in a timely manner to ensure that patients do not miss out on other courses of treatment. Clinicians also need to think about health resources. Immuno-oncology often involves significant expense, thus making it important to identify as quickly as possible that the drug is not having the intended effect.
Clinicians looking for guidance in answering these questions have few resources in the literature currently available. Some researchers have begun to retroactively audit studies published in recent years to identify predictors of response to provide a better guide for clinicians. Moving forward, however, it is important that researchers focus on providing better information for judging drug efficacy in patients.