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Standardization & Harmonization of Immuno-Oncology Toxicities

Eastman, Peggy

doi: 10.1097/01.COT.0000743548.22737.f7
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Immuno-Oncology Toxicities
Immuno-Oncology Toxicities:
Immuno-Oncology Toxicities

Immuno-oncology (IO) therapies have been steadily growing in importance and are used more and more frequently as an integral part of clinical cancer care. As previously reported by Oncology Times, a report from the Association of Community Cancer Centers (ACCC) showed that IO treatment is increasingly being given to patients in community settings, not just in academic cancer centers.

But the increased use of IO therapies has also brought increased toxicities and adverse events such as cytokine release syndrome (CRS). The Friends of Cancer Research (FOCR) held a webinar on the future of immunotherapies and cell therapies and released a detailed new white paper which addresses the need for “a standardized approach for diagnosing and reporting CRS and its manifestations in clinical trials, published literature, and in clinical practice.”

CRS is a T cell-mediated response driven by the immune system, which is seen in sepsis and recently in COVID-19, as well as in cancer care with immunotherapies and T-cell therapies. In affected patients, common symptoms include fever, hypotension, hypoxia, and the release of inflammatory cytokines.

The new white paper, Harmonizing the Definition and Reporting of Cytokine Release Syndrome (CRS) in Immuno-Oncology Clinical Trials, was written by a working group convened by FOCR. Jeff Allen, PhD, President and CEO of FOCR, said he hopes the white paper “will serve as a blueprint of sorts” as the IO field develops. The white paper makes specific recommendations on standardization and harmonization (see list on page 29).

Today is “a very promising time in this field,” noted Ned Sharpless, MD, Director of the National Cancer Institute (NCI), in keynote remarks for the online event. He noted that NCI has long been at the forefront of advances in IO, and said these advances have been especially noteworthy in melanoma and lung cancer. However, Sharpless said that “in many ways, this field is still in its infancy,” and there are many unanswered questions. These include how to manage toxicities when they occur and how best to combine IO agents with other therapies.

It is hard to overstate the beneficial impact of IO therapies on patients with cancer, noted FOCR working group member Meredith Chuk, MD, FAAP, Acting Associate Director for Safety in the Office of Hematology and Oncology Products in the Center for Drug Evaluation and Research at the FDA.

“This really has been a very robust development program,” and it is probably only going to get more so, Chuk stated. She noted there is a need to anticipate toxicities in the pre-market setting, which might lead to dose modifications on therapy labels. She added that it is important to capture patient symptoms and link them back to CRS; the ultimate goal is to increase patient safety by identifying those patients most likely to benefit, but also those most at risk of toxicity.

What is needed during this time of “explosive growth” in the IO field is a “call to action” for harmonized definitions and reporting of CRS, said working group member Bruce McCall, MD, Senior Safety Science Leader at Genentech. He pointed out that—as discussed in the white paper—it is necessary to differentiate CRS from acute infusion-related reactions. “We predict this is going to be an ongoing challenge” with IO products. Such differentiation is needed to ensure proper management of patients' treatment side effects, the white paper stresses.

Working group member P.K. Morrow, MD, FACP, agreed. “We've come far in developing IO therapies,” noting that advances have to be made in understanding IO toxicities, developing a harmonized way of characterizing CRS and achieving consistency in data collection so there are common datasets. Because a number of new treatment paradigms will involve combinations, it is especially important to tease out the side effects of each IO therapy to establish its safety profile, she said. The ACCC report on IO notes that “76 percent of currently active PD-1/PD-L1 trials are testing combination regimens of checkpoint inhibitors with other IO agents, targeted therapies, chemotherapies, or radiotherapy.”

What is needed is a common denominator for characterization of toxicities that can be used by different stakeholders in IO, said working group member Marcello Pasquini, MD, MS, Associate Professor of Medicine at the Medical College of Wisconsin; Senior Scientific Director for Clinical Trials at the Center for International Blood and Marrow Transplant Research (CIBMTR); and CIBMTR representative to the Worldwide Network for Blood and Marrow Transplantation.

Pasquini said the benefit of such a common denominator is that it can create a stepping stone to do analyses. He added that what is learned about IO therapies in the post-market setting can inform the pre-market setting. “This will help us make these products safer for patients,” he stressed.

Pasquini also noted that, while standardization of IO toxicities is needed, it should not be rigid, pointing out that as new agents come along, new elements may need to be incorporated into the characterization of CRS.

“These are therapies that are likely to evolve with time,” said Peter Marks, MD, PhD, Director of the FDA's Center for Biologics Evaluation and Research. He noted risk/benefit analysis is needed in IO because, while the FDA wants patients to be safe, it does not want to hold back the pace of development in the field. “This is an area where guidance that we issue will have to be continually updated,” he said of FDA guidance documents.

Standardization of data in IO is important to developers when considering payment strategies in the post-market setting for IO therapies, said Mark McClellan, MD, PhD, founding Director of the Duke-Margolis Center for Health Policy at Duke University, former administrator of the Centers for Medicare and Medicaid Services, and former FDA Commissioner. “Many of these therapies are complex,” said McClellan. “[Thus,] we need to collect a lot more data.”

Not only are IO registries needed to detect and record safety issues, but data are also needed to provide an understanding of how production modifications can occur, he stated.

Agreeing was Jennifer Malin, PhD, Senior Medical Director for Oncology and Genetics at UnitedHealthcare. She noted that from the payer standpoint, as new IO therapies come on the market, there is a need to consider how to pay for them—issues which include toxicities that may require hospitalization. Good data are required to make good payment decisions, emphasized Malin.

The new FOCR white paper states that the IO drug pipeline is growing rapidly and these therapies are “quickly being integrated into the standard of care for many cancers.” The paper focuses on establishing a standardized approach for defining and capturing CRS.

“The ultimate goal is to ensure accurate and consistent identification of CRS in patients receiving immunotherapies in clinical studies to aid in reporting; enable a more precise evaluation of the risk/benefit profile; support evidence-based monitoring and management of novel toxicities; and improve patient care and outcomes,” states the paper. It includes a table of evolving definitions and criteria for grading and managing CRS.

As previously reported in Oncology Times, the ACCC report on IO states that the IO field is expanding in part because, while most IO drug approvals have been based on data from clinical trials with patients who have late-stage or metastatic disease, “checkpoint inhibitors are emerging as feasible therapies in many adjuvant and neoadjuvant settings, such as in triple-negative breast cancer,” and ongoing trials are showing promise for IO in a number of other solid tumors.

Peggy Eastman is a contributing writer.

Guidance for Immuno-Oncology Toxicities

  1. Achieve alignment on defining and grading cytokine release syndrome (CRS). This should establish core principles for defining CRS that consider the therapeutic modality, symptom manifestation, timing, and response to intervention.
  2. Establish a strategy for assessing CRS over the course of a clinical development program. The FOCR white paper sets forth a decision tree for establishing population-level CRS risk during product development of an investigational agent.
  3. Ensure that harmonized data elements for characterizing CRS are used. The white paper includes a table representing a harmonized collection of discrete data elements.
  4. Use a consistent method for recording and reporting CRS events. This method should capture all the patient events and then link those adverse events that are signs and symptoms of CRS specifically to the CRS event.
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