The safety of combining immune checkpoint inhibitors and platinum-based chemotherapy for the treatment of solid tumors: A systematic review and network meta-analysis

Abstract

ObjectiveCombination treatment regimens consisting of both immune checkpoint inhibitors (ICI) and chemotherapeutic agents have emerged as the standard of care for a range of cancers. This network meta-analysis (NMA) examined the toxicity profiles and safety rankings of these different ICI-based combination regimens.MethodsThe PubMed, EMBASE, Web of Science, and Cochrane Library databases were searched for all randomized controlled trials (RCTs) published as of March 1, 2022 comparing two or more treatment regimens in which at least one arm was comprised of an ICI + platinum-based chemotherapeutic regimen. Treatment-related adverse events (AEs) of any grade and AEs of grade 3 or higher were the primary endpoints for this analysis, while specific AE types were secondary endpoints. This NMA combined both direct and indirect comparisons when analyzing odds ratios (ORs) and the surface under the cumulative ranking curve (SUCRA) for different ICI-based treatment regimens.ResultsIn total, 33 RCTs enrolling 19,012 cancer patients were included in this NMA. Of the analyzed regimens, avelumab + chemotherapy and camrelizumab + chemotherapy were associated with a significantly greater risk of AEs of any grade relative to ipilimumab + chemotherapy, durvalumab + chemotherapy, or pembrolizumab + chemotherapy. No significant differences in the risk of AEs of grade 3 or higher were observed when comparing different ICI regimens. Hepatotoxicity and pyrexia were the most common AEs associated with atezolizumab + chemotherapy treatment. Ipilimumab + chemotherapy was associated with a relatively higher risk of gastrointestinal and skin toxicity. Skin toxicity and hypothyroidism were the major AEs associated with nivolumab + chemotherapy. Fatigue and pneumonia were the most common AEs respectively associated with sugemalimab + chemotherapy and pembrolizumab + chemotherapy regimens.ConclusionsOf the evaluated regimens, camrelizumab + chemotherapy and avelumab + chemotherapy were associated with significantly higher rates of AEs of any grade, whereas durvalumab and sintilimab were relatively safe PD-L1 and PD-1 inhibitors, respectively, when administered in combination with platinum-based chemotherapy. However, none of the evaluated ICI + chemotherapy regimens exhibited any differences with respect to the incidence of grade 3 or higher AEs, offering guidance that may be of value in routine clinical practice.

Treatment-related adverse events of immune checkpoint inhibitors in clinical trials: a systematic review and meta-analysis

“…Several systematic reviews have illustrated the safety profiles of ICIs for cancer treatment at various sites (17,22,(28)(29)(30)(31)(32). Zhou et al (22) comprehensively assessed the incidences and safety profiles of trAEs among various combination therapies based on 161 RCTs and found that all-grade and grade ≥ 3 trAEs were higher for patients receiving PD-1 or PD-L1 inhibitors combined with chemotherapy or targeted therapies.…”

“…Xu et al (17) investigated the safety profiles of ICIs for esophageal cancer and found that most AEs of combined therapies were tolerable, and all-grade pneumonitis differed between the PD-1 and PD-L1 inhibitor groups. Mei et al (31) identified 33 RCTs and found that camrelizumab or avelumab combined with chemotherapy showed higher incidences of all-grade AEs, whereas durvalumab and sintilimab could be considered relatively safe PD-L1 and PD-1 inhibitors. Longo et al (16) identified seven RCTs and found that ICI-based combined treatment was associated with a high risk of grade 3-5 trAEs in patients with small cell lung cancer.…”

Isolated adrenocorticotropic hormone deficiency following immune checkpoint inhibitors treatment often occurs in polyglandular endocrinopathies

“…In our research, sintilimab, an anti-PD1 approved in China, was applied in most patients. Although thyroid dysfunction is the most commonly reported irAE of sintilimab [ 29 ], there is limited information available on the effect of thyroid antibodies by sintilimab. Therefore, it is reasonable to speculate that the low positive rate of thyroid antibodies in this study may be related to the use of different ICIs.…”

Fever of unknown origin associated with immune checkpoint inhibitors

“…Fever, caused by a wide variety of reasons, is frequently reported in cancer patients ( 37 ), and fever is one of the most prevalent adverse events after ICIs remedy ( 7 , 8 ). When immunotherapy is combined with other therapy patterns, the incidence of fever increases remarkably.…”

“…In general, FUO are classified as classic FUO, nosocomial FUO, immunodeficiency-associated FUO, and travel-associated FUO. Given that 1) ICIs are administered more frequently in cancer therapy; 2) pyrexia stands as one of the most common adverse events of ICIs ( 7 , 8 ); 3) patients treated with ICIs face challenges in identifying and discriminating the etiology of FUO, we believe that it is of crucial clinical significance to list ICIs-associated FUO as a separate category of FUO, which is defined as fever during ICIs administration in cancer patients with immune activation, cytokines secretion or pathogen reactivation.…”