TNBC accounts for approximately 10% to 20% of all BC cases and is associated with greater than 40% mortality rate within the first 5 years. Treatment options are limited, with neoadjuvant chemotherapy being the primary pharmacotherapy option. Due to the heterogeneity of the disease and differences in tumor sensitivity, various combination oncologic regimens have been tried, resulting in different outcomes and prognoses.
The advent of the PD-1 and PD-L1 inhibitors—two classes of immune checkpoint inhibitors—opened a new avenue of treatment for patients with this devastating disease. Atezolizumab, a PD-L1 inhibitor, was first approved in March 2019 to be used in combination with chemotherapy as first-line treatment in patients with PD-L1-positive advanced or metastatic TNBC, but its approval was withdrawn in August 2021. Currently, pembrolizumab is the only PD-1 inhibitor approved in the United States for high-risk, early stage, and locally recurrent unresectable or metastatic TNBC, although this does not preclude experimental or off-label use of other agents.
Investigators searched three databases—PubMed, Embase, and Cochrane Library—from March 1, 1980, through June 30, 2022, to evaluate the adverse events (AE) profile and safety of PD-1 or PD-L1 inhibitors in TNBC patients. To be included in the systematic review and meta-analysis, studies had to involve patients with TNBC; use of a PD-1 or PD-L1 inhibitor; include a control group; provide information of AEs; and be published in English. Case reports, case series, case-controlled studies, cohort studies, protocols, secondary research papers, animal studies, those that did not include a PD-1 or PD-L1 inhibitor, and duplicate articles were excluded.
Investigators identified nine articles—one that only used PD-1 inhibitors, three that used PD-1 inhibitors plus chemotherapy, and five that used PD-L1 inhibitors combined with chemotherapy—which included a total of 2,941 patients. Of these 2,941 patients, 1,055 had received the PD-L1 inhibitor, atezolizumab; 1,721 had received the PD-1 inhibitor, pembrolizumab; 165 had received the PD-1 inhibitor, durvalumab (off-label use); and 2,339 were in the control group. Data were available on AEs for eight of the nine papers in the www.clinicaltrials.gov database.
Among the most common serious AEs identified were neutropenia (3.15%), fatigue (2.5%), anemia (2.16%), adrenal insufficiency (1.7%), and alanine aminotransferase (ALT) elevations (1.47%). Serious immune-related AEs that occurred in fewer than 1% of patients included pneumonitis, hypothyroidism, and hyperthyroidism. A further analysis of serious pneumonitis found that when either PD-1 or PD-L1 inhibitors were combined with chemotherapy, the risk was increased over 2.5-fold (odds ratio [OR] 2.52; 95% CI, 1.02-6.26). The risk of serious hypothyroidism was greatest in the group who received a PD-1 inhibitor along with chemotherapy but was also elevated in those who received PD-1 and PD-L1 inhibitors versus chemotherapy. PD-1 inhibitor use was associated with a significantly increased risk of ALT elevations that was not attributed to chemotherapy (OR 1.63; 95% CI, 1.06-2.52). Risk of adrenal insufficiency was markedly elevated almost 19-fold in either the PD-1 or PD-L1 inhibitor group compared with the chemotherapy group (OR 18.81; 95% CI, 3.42-103.40).
Among the most frequent nonserious AEs reported were nausea, fatigue, anemia, diarrhea, headache, and arthralgias. The risk of hypothyroidism was 3.6 times higher (OR 3.63; 95% CI, 2.92-4.51) in the PD-1 or PD-L1 inhibitor groups than in the chemotherapy group; the risk was elevated for both groups separately but was higher in the PD-1 inhibitor group (OR 5.74; 95% CI, 1.48-22.20) than the PD-L1 inhibitor group (OR 3.85; 95% CI, 2.72-5.44). Pruritus and rash were more common with the ICIs than with chemotherapy. Fever also occurred more frequently with the PDL-1 inhibitors.
Additionally, a state-of-the-art review published in the December 2022 issue of JACC Cardio-oncology identified an association between ICI therapy and the development of accelerated atherosclerosis and atherosclerotic cardiovascular events. More information is needed about potential cardiovascular risk. At this time, the role of statins and proprotein convertase subtilisin/kexine type 9 inhibitors needs to be further defined in the management of these conditions.
This systematic review and meta-analysis, along with the state-of-the art review, provide insight into the AE profile of PD-1 and PD-L1 inhibitors when used in TNBC. Pharmacists can use this information to monitor and counsel patients with TNBC who are receiving these agents.
The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.
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Published January 10, 2023