Cancer therapies: Immune checkpoint inhibitors may kill you

October 21, 2018 – In a study published online September 13 in JAMA Oncology, the authors just reminded us of the fact that besides all hype about immune checkpoint inhibitors (ICIs) in the cancer therapy field, they can be associated with rare, yet sometimes frank fatal adverse drug reactions (fADRs). The worldwide increase in the use of ICIs across most cancer types justifies the importance of defining the most serious unwanted effects and alerting oncologists, emergency department physicians, critical care providers, other specialists, and most important of all, patients, about their existence and occurrence in the treated patient population.

The present study explored multiple sources to analyse data pertaining to immune-related adverse drug reactions (irADRs) associated with immune checkpoint inhibitors (ICIs) targeting either cytotoxic T lymphocyte antigen–4 (CTLA-4) or programmed cell death–1/ligand-1 (PD-1/PD-L1). One of the key sources of the data probed was the World Health Organization (WHO) based VigiBase, hosted and maintained at the Uppsala Monitoring Center (UMC), which contains more than 16 million reports of individual safety case episodes and adverse drug reactions.

Of course, fatal effects from immune checkpoint inhibitors (ICI) are most likely being rare; however, a variety of serious unwanted effects with these drugs may occur (and should even be expected to occur),  may affect any otherwise healthy organs, and stem from activation of autoreactive T cells damaging host tissues, i.e., the treatment with ICIs may activate unwanted, sometimes fatal, autoimmunity reactions in predisposed patients. The study also shows that these events generally occur very early after therapy initiation and with marked distinctions between clinical ICI regimens.

The study investigators screened 31’059 individual case reports of ICI-related events, and identified in the process 613 fatal ADRs. Fatal ADRs identified in association with the PD-1/PD-L1 inhibitors included fatal pneumonitis, hepatitis, colitis, neurologic events, and myocarditis. The drugs with which these case reports were associated included Ipilimumab (Yervoy) monotherapy (n = 193); PD-1/PD-L1 inhibitors such as Pembrolizumab (Keytruda) or Nivolumab (Opdivo) (n = 333), and the combination of a PD-1/PD-L1 inhibitor plus an anti-CTLA-4 agent (n = 87). Most of these patients suffered from a single serious unwanted effect causing death. Patients who received a combination of ICIs were more likely to have multiple concurrent serious ADRs than those who received monotherapies.

Academic Centers

The investigators also reviewed all patients treated with an ICI at seven academic centers. In this cohort of 3545 patients, the fatality rate was 0.59%. The events were fairly evenly distributed among those treated with Ipilimumab (Yervoy), those treated with an anti-PD-1 agent, and those who received a combination of PD-1/CTLA-4 blockade. In the academic center analysis, the median time to fADR onset was 15 days following treatment initiation, and the median time from symptom onset to death was 32 days. The nature of the event also varied. Cases of fARDs ranged from those that followed a fulminant course with a single hospitalization prior to death (62%) to those that followed a more protracted course in which the patient’s condition stabilized and the patient was discharged from hospital before the condition worsened (38%). An analysis of pooled data from the seven academic centers and those from the Vigilyze database showed that the median time to the onset of an unwanted event was relatively early after treatment initiation, at 40 days for ipilimumab, 40 days for the PD-1/PD-L1 inhibitors, and 14.5 days for an ICI combination. The same analysis showed that for the three regimens, the median time to death was 64 days, 43 days, and 35 days after initiation of treatment, respectively.

Clinical Trials

The researchers also analyzed published clinical trial data of the anti-PD-1 agents, the anti-PD-L1 agents, and the anti-CTLA-4 drugs, as well as combinations of these classes of agents. In 112 clinical trials, 19,217 patients were treated with one or a combination of these agents, and 122 fatal drug-related ADRs were documented. The frequency of fatal  events ranged from 0.36% for PD-1 inhibitors, 0.38% for PD-L1 inhibitors, 1.08% for anti-CYLA-4 agents, and 1.23% for the combination of a PD1/PD-L1 plus a CTLA-4 agent.

Risk / Benefit  Considerations

The study points out that although the Vigilyze database revealed more than 600 fatal events that were linked to ICI use, the risk of a fatal ADR remains very low for individual patients with advanced cancer. The study authors compared the risk for fatal ADR associated with ICIs with mortality risks associated with other commonly used oncology agents.

Thus, for example, the use of platinum-based doublet chemotherapy is associated with a 0.9% fatality rate, and the fatality rate associated with the use of targeted therapy with either angiogenesis or tyrosine kinase inhibitors ranges from 0 to 4%.  Moreover, a treatment-related death rate of 0.36% to 1.23% is dramatically lower than the near 100% fatality rate for metastatic solid tumors, as the authors of the study rightly pointed out.

This was a large study supported by the Cancer ITMO of the French National Alliance for Life and Health Sciences (AVIESAN), the National Institutes of Health, the James C. Bradford Jr Melanoma Fund, and the Melanoma Research Foundation (MRF).

See also this introductory video to immune checkpoint inhibitory therapy. But keep in mind, that unlocking the breaks on the immune system als bears the fatal risk for some patients predisposed to potentially fatal autoimmune reactions.