Treatment with an immune checkpoint inhibitor (ICI) within 90 days of undergoing radiotherapy (RT) did not increase the risk of serious adverse events (AEs) in patients with cancer, according to results from a pooled analysis published in JAMA Oncology.
“Among the newer agents widely used in recent years are the immune checkpoint inhibitors (ICIs), which are approved by the FDA for the treatment of numerous advanced malignant neoplasms. The toxicity profiles of these agents are well characterized and include immune-mediated adverse events (AEs) affecting the lungs, liver, thyroid, gastrointestinal tract, and, less commonly, the heart and central nervous system, among other organs. Given emerging data suggesting systemic immune effects of radiation and redundancies in the mechanisms of ICI- and RT-induced toxic effects, there exists potential for enhanced toxicity when combining these agents,” according to researchers led by Mitchell S. Anscher, MD, of the U.S. Food and Drug Administration, Silver Spring, Maryland.
“However, little data are available to guide clinicians on ICI use in conjunction with RT. To address this question, we performed a pooled analysis of patient-level data from prospective trials in the FDA databases,” they added.
Anscher and colleagues used patient-level data from 68 prospective trials of ICIs included in the FDA’s databases to identify two cohorts of patients, comprised of a total of 16,835 patients: those who underwent RT 90 days prior to initiating ICI treatment (n=1,733) and those who did not (n=13,956).
They used these patients to conduct their 1:1 propensity score-matched analysis. Most patients were White (79.7%) men (62.1%) younger than 65 years old (56.1%) and had an ECOG performance status of 0 or 1. Lung, melanoma, kidney, head and neck, and bladder cancers were the most common primary tumors. All patients received one of the following ICIs: atezolizumab, avelumab, cemiplimab, durvalumab, ipilimumab, nivolumab, or pembrolizumab.
The primary outcome was the incidence and severity of adverse events, but authors noted that “[b]ecause all analyses are exploratory (ie, not preplanned and no alpha allocated), assessment for statistical significance of the differences between groups was not considered appropriate.”
The rate of overall adverse events was similar in patients who underwent RT and those who did not, with an average absolute difference in rates of adverse events of 1.2%, which ranged from 0% for neurologic events to 8% for fatigue. There were no differences in the incidence of grade 3/4 adverse events between the groups, with an absolute difference that ranged from 0.01% to 2%.
In analyses both before and after propensity score matching, the most common grade 3/4 adverse events were fatigue, diarrhea, neutropenia, and pneumonitis, but the incidence rates were all below 5%. For example, before propensity score matching, fatigue (the most common of these) occurred in 4.8% of patients who did not undergo RT compared with 4.8% of those who underwent RT at 90 days or sooner after immunotherapy, and 2.8% of those undergoing RT more than 90 days later. similarly, pneumonitis was seen in 1.1% versus 1.9% versus 1.2% of these patients, respectively.
The two most common causes of treatment discontinuation were pneumonitis, which occurred in 1.4% of patients who did not receive RT, 2.7% of those who received RT at 90 days or less after immunotherapy, and 1.1% of those undergoing RT longer than 90 days out; and colitis, seen in 1.3%, 1.2%, and 0.6% of patients, respectively.
But, because there were too few patients who had undergone RT to conduct a “meaningful analyses,” noted Anscher and fellow researchers, they also compared the incidence of adverse events with or without RT in the three largest ICI treatment subgroups. These included patients treated with anti-programmed cell death 1 (anti-PD-1), anti-PD-1 plus anti-cytotoxic T-lymphocyte associated protein 4 (anti-CTLA-4), and anti-programmed cell death 1 ligand 1 (anti-PD-L1) agents. They found the following:
- Colitis was more common in patients treated with anti-PD-1 plus anti-CTLA-4 without prior RT compared with those treated with this immunotherapy combination after RT.
- Fatigue was more common in patients who received prior RT in all three immunotherapy treatment groups.
- Pneumonitis was more common only in patients who had received previous RT and an anti-PD-L1 agent.
- Endocrinopathies were more common in patients treated with an anti-PD-L1 agent after RT compared with those receiving no previous RT; they were less common in patients treated with anti-PD-1 plus anti-CLDA-4 agents without RT compared to those undergoing previous RT.
“Taken together, these data do not demonstrate a large increase in risk of AEs when RT and ICIs are used in combination. The results in the literature also support the findings of the present study. While we did find a very slight increase in the risk of pneumonitis, thrombocytopenia, kidney AEs, and fatigue in RT ≤90 patients and a similarly small increased risk of pneumonitis in RT>90 patients, the absolute magnitude of the risk increase was very small, and most AEs were grade 1 to 2. Hematologic AEs, particularly lymphopenia, might adversely influence the immunologic response to ICIs. This would suggest the need to minimize radiation to bone marrow in patients who will receive ICIs. Future studies also should evaluate whether all low-grade AEs are truly AEs,” concluded Anscher and colleagues.
In their colorfully entitled editorial, “When radiotherapy and immunotherapy dance—Who leads so as not to step on toes?“, Fiyinfolu Balogun, MD, PhD, of Memorial Sloan Kettering Cancer Center, New York, and David Raben, MD, of the University of Colorado, Aurora, began with a query:
“Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of several cancers, significantly increasing survival in advanced disease. A substantial proportion of these patients have received radiotherapy (RT) prior to or after ICI treatment. We have aggressively moved toward strategies combining RT and immunotherapy concurrently or sequentially in oligometastatic disease. Importantly, this strategy has gravitated to earlier stages of disease, with some outstanding successes. What have we learned about the toxicity implications associated with this combination, and how might we mitigate harm to the patient?”
More studies are needed, they added, to explore the myriad factors that may affect outcomes and toxicities. Nevertheless, concluded Balogun and Raben, these results from Ascher et al support the safety of combining RT and ICIs in treating cancer.
“This review of the compendium of data from the U.S. Food and Drug Administration registry provides additional assurances that sequential RT and ICIs is tolerable and safe,” they wrote. “It suggests that when RT leads immunotherapy, the dance goes reasonably smoothly. The importance of understanding the toxicity from combined ICI and RT rises with the expansion of immunotherapy to the adjuvant/neoadjuvant setting as it relates to sequencing, volumes treated, and the dose per fraction of RT.”
Study limitations include its retrospective nature, a lack of data on RT treatment regimens (which may have affected immune responses and injury to normal tissues), missing data on previous therapies administered, and the short time frame of AE collection.
“As the authors alluded to, a notable limitation of this evaluation lies in the absence of key RT details such as dose per fraction, treatment site, and volumes irradiated. This can be critical information that affects both acute and long-term toxic effects, as well as potentially contributing to chronic immunosuppression depending on the volumes that include uninvolved lymph node basins,” noted Balogun and Raben.
Administration of an immune checkpoint inhibitor (ICI) within 90 days following radiotherapy (RT) was not associated with an increased risk of serious adverse events.
Pooled analysis of patient-level data from clinical trials finds similar incidence of AEs, whether or not patients received RT prior to immune checkpoint inhibitor therapy.
Liz Meszaros, Deputy Managing Editor, BreakingMED™
Anscher and Balogun reported no disclosures.
Raben reported being previously employed by Genentech.
Cat ID: 120
Topic ID: 78,120,730,120,24,26,835,935,192,925,482