Accurately attributing toxicity with combination regimens: An emerging practice challenge
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The use of immune checkpoint inhibitors in cancer care has expanded exponentially over the last few years.
To date, checkpoint inhibitors (CPIs) have 17 indications across a variety of cancer types and unique genomic scenarios.
In an article published last year in JAMA Network Open, Haslam and Prasad estimated that 43.63% of U.S. patients with advanced cancer were eligible for a CPI in 2018. Also, they found that CPI use in cancer care is showing no signs of slowing, as clinical trials using CPIs were up 600% from 2015 to 2017, from 215 to more than 1,500 trials.
CPIs have become increasing desirable therapeutic options given their general tolerability and potential for inducing durable responses and prolonging survival. Initially given as single agents, CPIs are increasingly being used in combination with other cancer treatments such as chemotherapies and targeted therapies.
Individually, each class of cancer therapies has its own benefits and limitations. Targeted therapies and chemotherapies tend to induce responses in a greater number of patients, although duration can be limited. CPIs have lower response rates but the responses can be more durable.
As CPIs are safe, tolerable and effective as monotherapy, combining them with other agents can engage multiple mechanisms of action to simultaneously and potentially synergistically attack cancer.
According to Heinhuis and colleagues, preclinical studies suggest that “combining CPIs with other treatment modalities may lead to improved immunological conditions in the tumor microenvironment and could thereby enhance the antitumor immune response, even in tumor types that are so far unresponsive to CPI monotherapy.”
Multimodal combination therapy regimens are already approved in several cancer types and are being studied within clinical trials in a variety of others.
But when therapies that could cause overlapping adverse events (AEs; ie, diarrhea, endocrinopathies, elevation in liver function tests) are being used in combination, how can clinicians know which therapy may be causing a specific toxicity?
A detailed evaluation of individual therapy or clinical features can provide telling information that may aid in identification of the causative therapy.
Therapy half-life
Awareness of drug half-lives can be critical in helping to identify the cause of specific AEs. CPIs, as antibodies, generally have long half-lives, the majority being 20 or more days.
Additionally, CPI receptor occupancy far exceeds the duration of the CPI drug half-life. Brahmer and colleagues showed the PD-1 receptor occupancy remains at approximately 80% for nearly 3 months after a single dose of nivolumab (Opdivo, Bristol Myers Squibb).
Targeted therapy and chemotherapy half-lives, however, are typically are much shorter, ranging from a few hours to a few days.
Putting this half-life knowledge into practice by holding the targeted therapy or chemotherapy first, given the shorter half-life of these agents, the clinician should see improvement in the toxicity within the first few days if the toxicity is related to the non-CPI agent. If there is no improvement in symptoms, the clinician must consider an immune-related adverse event (irAE) from the CPI as a differential and work-up accordingly.
CPIs should not be readministered until an irAE is fully ruled out. Importantly, if the patient is toxic-appearing or severely ill, the clinician should assume the toxicity is an irAE and treat it as such until proved otherwise. IrAEs, particularly those that are high grade, are often complex and are likely to require management from dedicated subspecialists.
Timing of onset
AEs from both CPIs and non-CPI agents typically present within the first few weeks to months of therapy initiation. Toxicities that develop several months to years after starting therapy should be evaluated critically to rule out a delayed-onset irAE, as it would be atypical for new toxicities to develop so late from targeted or chemotherapies. Identification and classification of toxicities as delayed-onset irAEs is an emerging topic and a previously underrecognized phenomenon given the field’s lack of long-term experience with CPIs.
Physical inspection/symptom presentation
Physical exam, inspection and appraisal of symptoms can provide the clinician with key clinical information in determining the etiology of the AE. This can be done through extensive questioning regarding the presentation and course of symptoms, a detailed physical exam and attention to pertinent clinical information, ie, personal or family history of autoimmune disorders, comprehensive review of relevant labs/diagnostics, and awareness of other potential contributing conditions or therapies.
For instance, symptom presentation may vary between irAEs and other therapy-induced AEs. CPI-induced diarrhea/colitis can present as abdominal pain, distension, bloating, hematochezia or mucus in the stool, whereas targeted therapy-induced diarrhea often presents more simply as loose or liquid stool with bowel urgency and/or frequency.
Response to intervention
Given that irAEs occur as a result of inflammation of healthy tissue from an overactive immune response, interventions short of CPI therapy holds and immunosuppressive agents are unlikely to improve symptoms. IrAEs, particularly high-grade toxicities, typically require systemic steroids and possibly additional immunosuppressants, such as antitumor necrosis factor therapies.
To illustrate, recommended treatments for targeted and chemotherapy-induced diarrhea classically include anti-diarrheal or antimotility agents, probiotics, psyllium fiber supplements and dietary modifications. Although these agents may slow the gut motility or help form the stool, they will not treat the root cause of CPI-induced diarrhea, which is inflammation of the colon. If little or no improvement occurs after starting traditional AE management strategies, the clinician should consider an irAE as a differential.
Incidence/severity of AEs
It is beneficial for the clinician to be aware of the incidence of toxicities, including those that are high grade (grade 3 to grade 4). This can be accomplished by reviewing the prescribing information of each therapy.
Although evaluation using these measures can aid in identifying the cause of the AE, it does not substitute for toxicity-specific labs and diagnostics that may be required to make a formal diagnosis. Further, although therapies should be considered as possible causes of toxicities, the clinician must also consider other nontherapy-related medical causes.
It is critical for the clinician to attribute toxicities quickly and accurately, as treatment and management varies widely based on causative agent. Delay in accurate AE attribution may have considerable implications on quality of life, morbidity and mortality, and health system reimbursement.
References:
Brahmer JR, et al. J Clin Oncol. 2010;doi:10.1200/JCO.2009.26.7609.
Haslam A and Prasad V. JAMA Netw Open. 2019;doi:10.1001/jamanetworkopen.2019.2535.
Heinhuis KM, et al. Ann Oncol. 2019;doi:10.1093/annonc/mdy551.
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