Both Patients and Clinicians Face Challenges in Recognizing and Reporting Immune-Related Adverse Events


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Keith T. Flaherty, MD

Keith T. Flaherty, MD

Padmanee Sharma, MD, PhD

Padmanee Sharma, MD, PhD

The publication of ASCO’s toxicity management guidelines for immune checkpoint antibodies by Brahmer and colleagues,1 reviewed in this issue of The ASCO Post, has been long awaited, considering more than 15 distinct indications have been granted by the U.S. Food and Drug Administration (FDA). The first came in 2011 with the FDA approval of ipilimumab (Yervoy), an antagonistic antibody against the cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) inhibitory molecule. Based on improvements in overall survival over standard therapies in most of those cases, these agents are here to stay.

The clinical success of anti–CTLA-4 as an immunotherapeutic agent that conferred a survival benefit to patients with metastatic melanoma led to a new class of oncology agents termed immune checkpoint therapy, including programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors, which have produced widespread clinical benefit never before witnessed in the field of cancer immunotherapy. A growing body of evidence supports the use of anti–CTLA-4 in combination with PD-1/PD-L1. PD-1 antibodies alone present the cancer treating community with enough of a challenge in terms of learning about a totally unique type of toxicity, but combined CTLA-4 blockade significantly heightens the need for immunotherapy toxicity research and management tools beyond broad and static guidelines.

Toxicity Recognition Evolves

The first-generation management guidelines developed by Brahmer et al largely reflect the evolution of toxicity recognition within the clinical trials that established their benefit. As with so many oncology clinical trials, the threshold for intervention and dose modification has been severe toxicity (Common Terminology Criteria for Adverse Events [CTCAE] grade 3 and 4). And, absent molecular insights into the immune-related toxicities that account for the vast majority of adverse events with these agents, medical intervention with corticosteroids followed by tumor necrosis factor–blocking antibodies became the templated approach.

All personnel who may be contacted by a patient or family member should become knowledgeable of immune checkpoint therapies and their toxicities to react with appropriate escalation in monitoring or intervention.
— Keith T. Flaherty, MD and Padmanee Sharma, MD, PhD

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For those who have given these agents in clinical trials and clinical practice for several years now, it is apparent there are many patterns of immune-related toxicity emergence and nuances to management that seem inadequately captured by the toxicity data tables that populate the published literature and drug labeling. Examples include differences in the time course of adverse event emergence over time, change in the pace of immune-related toxicity onset based on treatment regimen (PD-1/PD-L1 monotherapy vs PD-1/CTLA-4 combination, for example), and co-occurring toxicities that might signal the likely emergence of severe toxicity more so than single events. Current clinical practice among immunotherapy experts leverages instincts that are informed by watching variations on these themes and a desire to intervene before severe toxicity manifests. All -oncology practitioners, including immuno-oncology experts, need tools that will accelerate dissemination of expert practice and, ultimately, data-informed improvements in toxicity recognition and management.

Challenge in Reporting Toxicity

Toxicity reporting in clinical trials and in routine practice is limited by several factors. Patients are systemically interviewed regarding symptoms at face-to-face office visits, which may occur once every several weeks. Interim reporting of toxicity symptoms depends on successful education of patients and their care providers regarding the priority of reporting seemingly innocuous symptoms. It is well known that cancer patients, and particularly those in clinical trials, are wary of reporting all treatment-emergent symptoms for fear that life-prolonging treatment will be withheld. Education regarding this issue is an ongoing process through the course of therapy and is more resource--intensive than for many cancer therapies. Similarly, all personnel who may be contacted by a patient or family member should become knowledgeable of immune checkpoint therapies and their toxicities to react with appropriate escalation in monitoring or intervention.

Immune checkpoint antibody toxicities typically emerge in a subacute fashion over days to weeks. Compared with the typical clinical trial data-capture process, detection of these emerging events by practitioners requires a higher resolution of patient reporting than office visits timed with treatment administration. But, given the time constraints of all care providers, daily phone calls are hardly practical for the large and growing fraction of a typical oncology practice with patients to whom these therapies are being administered. Diaries that are reviewed only after toxicities have progressed from mild to moderate obviate the ability to develop early recognition and intervention strategies. Immunotherapy toxicity management is arguably the oncology field’s best use case for technology development to optimize clinical care and fuel research.

With better data will come better clinical care and more sharply focused interventional studies to improve on the current state of toxicity mitigation.
— Keith T. Flaherty, MD and Padmanee Sharma, MD, PhD

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The goal of optimal immunotherapy toxicity monitoring must shift from recognition and treatment of severe toxicity to development of pattern recognition associated with a very high likelihood of evolution to severe toxicity and early intervention. This will not be achieved by promulgation of our current recognition and management standards. In fact, severe toxicity prediction will likely require both investigations of currently hypothesized predictors (such as the emergence of moderate skin and intestinal toxicities within the first two doses of treatment) and unbiased analysis of higher-resolution symptom-reporting data.

In parallel with improved data capture, the immuno-oncology field has inadequately focused on the immuno-biology behind immune checkpoint–associated toxicity. It is a striking fact that the most commonly affected tissues are skin, large intestine, liver, and endocrine glands. Although they are well-known sites of immune attack in the setting of immune-related toxicities, it is striking how much more reversible immune checkpoint toxicities are compared with spontaneous autoimmune events. In this difference, immunosuppressive mechanisms must be better understood and leveraged for the purpose of developing more precise mitigation strategies if not prevention.

Long-Term Commitment to Research

The challenges that must be overcome to optimize immunotherapy toxicity management are significant, but the benefits associated with these therapies support a long-term commitment to research in this area. Discerning immunotherapy-associated toxicity will only be made more difficult by the fact that in several indications, PD-1/PD-L1 antibodies are given with other classes of cancer therapeutics. But the learning process starts with leveraging currently available tools and technology that have been largely developed outside of the health-care industry. With better data will come better clinical care and more sharply focused interventional studies to improve on the current state of toxicity mitigation. ■

Dr. Flaherty is Professor of Medicine, Harvard Medical School; Director, Henri and Belinda Termeer Center for Targeted Therapy; Director of Clinical Research, Massachusetts General Hospital Cancer Center, Boston. Dr. Sharma is Professor, Department of Genitourinary Medical Oncology and Department of Immunology, Division of Cancer Medicine; Scientific Director, Immunotherapy Platform, and Co-Director Parker Institute for Cancer Immunotherapy, MD Anderson Cancer Center, Houston.

DISCLOSURE: Dr. Flaherty has received honoraria as a consultant/advisor to Merck, BMS, Roche, Amgen, and Incyte. Dr. Sharma has received honoraria as a consultant/advisor to Constellation, Jounce, Kite Pharma, Neon, BioAtla, Pieris Pharmaceuticals, Oncolytics Biotech, Merck, BioMx, Forty-Seven, Polaris, and Apricity; has stock or other ownership in Jounce, Neon, Constellation, Oncolytics, BioAtla, Forty-Seven, Apricity, and Polaris; and her spouse is a consultant for Jounce, Kite Pharma, Neon, Amgen, Forty-Seven, Apricity, and Polaris, and owns stock in Jounce, Neon, BioAtla, Forty-Seven, Apricity, and Polaris.

REFERENCE

1. Brahmer JR, Lacchetti C, Schneider BJ, et al: Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. February 14, 2018 (early release online).


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