Clinical trials are essential for turning cancer research breakthroughs into lifesaving treatments for patients, allowing doctors to learn which drugs work and which do not. The criteria used to evaluate patient responses play a huge part in whether drugs will be approved and made available to more patients.
With that in mind, last November the Lymphoma Research Foundation (LRF) invited the Cancer Research Institute (CRI) and leadership from CRI’s Cancer Immunotherapy Consortium to co-host a workshop to improve these criteria specifically for lymphoma patients treated with immunotherapy. The result of that workshop, published in August in the journal Blood, is LYRIC (Lymphoma Response to Immunomodulatory Therapy Criteria), a new set of guidelines that aims to provide doctors with a better way to gauge immunotherapy responses in these patients.
Until recently, the traditional response criteria―RECIST for solid tumors, and the Lugano classification specifically for lymphoma―were designed solely with chemotherapy and radiation therapy in mind. These treatments usually elicit straightforward effects: either the tumors grow or they don’t. These responses also occur relatively soon after treatment. As a result, if a patient’s combined tumor burden has gotten significantly bigger at any point after treatment, their disease is judged to have progressed, and they are usually taken off of the treatment.
However, responses to immunotherapy are often more complex. Sometimes immunotherapy’s anti-tumor effects can be delayed, since it acts on immune cells rather than on cancer cells directly. This can allow tumors to get bigger before they eventually shrink or stop growing. Additionally, the activation of an immune response against cancer, during which immune cells infiltrate tumors and cause them to swell up, can result in “tumor flares” that make it appear the tumors are growing.
This phenomenon―called “pseudoprogression”―can make it appear that a treatment isn’t working, when it actually is or when it could still be effective if given more time. And because the old guidelines don’t account for this “pseudoprogression” associated with immunotherapy, it can cause patients to be taken off treatment prematurely, before they have a chance to fully benefit from it. Clearly, this poses a problem. Luckily, CRI scientists have worked to address it ever since the promise of immunotherapy began to be realized.
It started several years ago, when a group led by Jedd Wolchok, M.D., Ph.D.―an associate director of CRI's Scientific Advisory Council―and Axel Hoos, M.D., Ph.D.―the co-director of CRI’s Cancer Immunotherapy Consortium and also a member of our Scientific Advisory Council―developed improved guidelines for gauging immunotherapy responses in solid tumors. This method is now known as the immune-related response criteria (IRC or also irRC). However, the considerations for solid tumors are different than those for tumors of the blood like lymphoma. Therefore, Dr. Hoos along with Bruce Cheson, M.D., F.A.C.P., FAAAS, Georgetown University Hospital Lombardi Comprehensive Cancer Center, and past chair of LRF’s Scientific Advisory Board, and others sought to develop new guidelines for lymphoma in the spirit of IRC, which they have named LYRIC.
“As lymphoma treatment options continue to advance, it is imperative that any evaluation metrics keep pace with our evolving understanding of this disease and its treatment,” said Dr. Cheson. “The benefits to the treatment landscape promised by immunotherapy deserve a more inclusive assessment than what we currently use, and we are proud to say that LYRIC will be a major step forward in creating more accurate patient response measurements for lymphoma patients undergoing immunotherapy.”
LYRIC addresses the same concerns the IRC did, but with some modifications that take into account the fluid nature of lymphoma tumors. The most novel aspect of LYRIC is the creation of a new category called “indeterminate response” (IR) that reflects the many uncertainties that still exist regarding how best to evaluate these irregular immunotherapy responses in lymphoma patients, as well as when it is best to evaluate them.
This IR category will allow doctors to more fully examine and interpret these responses, and in the meantime ensure that lymphoma patients who might still potentially benefit from immunotherapy can stay on the treatment until their next analysis can clarify the reality of the situation. Additionally, they stress that while LYRIC is provisional because the data isn’t there yet to validate its effectiveness, it’s an important first step that provides a framework to “categorize, report, and manage” the responses in this clinical gray area. As more and more data are obtained using LYRIC’s guidelines, it will hopefully enable doctors to better distinguish between true progression and pseudo-progression, so that they can “maximize the early detection of treatment failure while limiting the possibility of discarding a useful treatment too soon.”