A systematic review of adverse events in randomized trials assessing immune checkpoint inhibitors

Abstract

The advent of immune checkpoint‐inhibitors (CPI) has transformed treatment for several cancer types. This review was performed to assess the rate of adverse events (AEs) associated with the use of CPI, alone or in combinations. A review of AEs reporting quality was also performed. All publications of Randomized Clinical Trials (RCTs) assessing CPI published before December 2017 were included. To investigate the quality of AEs reporting, a set of items was defined based on the 2004 CONSORT harms extension statement. Rates of Grade 5, serious, and study‐withdrawal related AEs were collected in each treatment category. Specific immune related AEs (irAEs) were also collected when available. Pooled estimates of adverse event rates were calculated by using generalized linear mixed model. A total of 35 RCTs including 16,485 patients were included. The overall quality of AEs reporting was satisfactory, but items pertaining to methods of data collection and analysis were infrequently reported. Grade ≥ 3 AEs were reported for 14% (95% CI 12–16) of patients treated with PD(L)‐1 inhibitors, 34% (95% CI 27–42) of patients treated with CTLA‐4 inhibitors, 55% (95% CI 51–59) of patients on CPI combinations and 46% (95% CI 40–53) of patients on immunotherapy‐chemotherapy combination. The profile of irAEs was different among the treatment categories. The use of CPI, especially in combination, is associated with significant rates of Grade ≥ 3 AEs. Healthcare planning should anticipate the expected high number of patients presenting with irAEs in the future.

Immune-Related Adverse Events in the Setting of PD-1/L1 Inhibitor Combination Therapy

“…A systematic review of 35 clinical trials showed a different pattern of toxicity regarding frequency and specific organ involvement depending on the type of therapeutic scheme that was administered (i.e., PD‐1/L1 inhibitor monotherapy, CTLA‐4 monotherapy, immunotherapy combination therapies, or concomitant administration of immunotherapy and chemotherapy; Fig. ) . The current guidelines for management of irAEs, based largely on toxicities with CTLA‐4 and PD‐1/L1 monotherapies, will likely require revision as experience with combination therapies continues to accrue.…”

“…Frequency of (A) any grade and (B) grade 3/4 adverse events in clinical trials of PD‐1/L1 inhibitors, CTLA‐4 inhibitors, immunotherapy combinations, and chemotherapy plus immunotherapy combinations . *, Myositis and mucositis not included because these adverse events were NA for all groups except for PD‐1/L1 inhibitor.…”

Mechanisms of checkpoint inhibition-induced adverse events

“…Anti‐CTLA‐4‐associated irAEs are generally more severe, and trend towards (entero‐)colitis and hypophysitis. Hyperthyroidism and pneumonitis are more common with anti‐PD‐1/PD‐L1 targeting , with pembrolizumab having been reported to frequently cause vitiligo, implying tolerance break and autoimmunity . Interestingly, the incidence of irAEs appears to increase with the administered dose of ipilimumab, but not anti‐PD‐1 agents .…”

Management of immune checkpoint inhibitor‐related adverse events: A review of case reports

“…Several organ specific AE rates varied among tumor sites. The most frequent AEs of any grade with PD‐1/PD‐L1 inhibitors and CTLA‐4 inhibitors alone were diarrhea (11% and 36%), fatigue (21% and 25%) pruritus (15% and 25%) and rash (10% and 23%) . The frequency of colitis ranged from 8% to 22%.…”

“…The most frequent AEs of any grade with PD-1/PD-L1 inhibitors and CTLA-4 inhibitors alone were diarrhea (11% and 36%), fatigue (21% and 25%) pruritus (15% and 25%) and rash (10% and 23%). 3 The frequency of colitis ranged from 8% to 22%. It was reported that hypophysitis can affect up to 10% of patients treated with anti-CTLA-4 inhibitors.…”