Comprehensive adjusted outcome data are needed to assess the impact of immune checkpoint inhibitors in cancer patients with COVID‐19: Results of a systematic review and meta‐analysis

Abstract

Background Determining how prior immune checkpoint inhibitor (ICI) therapy influences outcomes in cancer patients presenting with COVID‐19 is essential for patient management but must account for confounding variables. Methods We performed a systematic review and meta‐analysis of studies reporting adjusted effects of ICIs on survival, severe events, or hospitalisation in cancer patients with COVID‐19 based on variables including age, gender, diabetes mellitus, hypertension (HTN), chronic obstructive pulmonary disease, and other comorbidities. When adjusted effects were unavailable, unadjusted data were analysed. Results Of 42 observational studies (38 retrospective), 7 reported adjusted outcomes for ICIs and 2 provided sufficient individual patient data to calculate adjusted outcomes. In eight studies, adjusted outcomes were based on ≤7 variables. Over all studies, only one included >100 ICI patients while 26 included <10. ICIs did not alter the odds ratio (95%CI) (OR) of death significantly (random effects model), across adjusted ( n = 8) [1.31 (0.58–2.95) p = 0.46; I 2 = 42%, p = 0.10], unadjusted ( n = 30) [1.06 (0.85–1.32) p = 0.58; I 2 = 0%, p = 0.76] or combined [1.09 (0.88;1.36) p = 0.41; I 2 = 0%, p = 0.5)] studies. Similarly, ICIs did not alter severe events significantly across adjusted ( n = 5) [1.20 (0.30–4.74) p = 0.73; I 2 = 52%, p = 0.08], unadjusted ( n = 19) [(1.23 (0.87–1.75) p = 0.23; I 2 = 16%, p = 0.26] or combined [1.26 (0.90–1.77) p = 0.16; I 2 = 25%, p = 0.14] studies. Two studies provided adjusted hospitalisation data and when combined with 13 unadjusted studies, ICIs did not alter hospitalisation significantly [1.19 (0.85–1.68) p = 029; I 2 = 5%, p = 0.40]. Results of sensitivity analyses examining ICI effects based on 5 variables were inconclusive. Certainty of evidence was very low. Conclusions Across studies with adjusted and unadjusted results, ICIs did not alter outcomes significantly. But studies with comprehensive adjusted outcome data controlling for confounding variables are necessary to determine whether ICIs impact COVID‐19 outcomes in cancer patients.

Anti-PD-L1 therapy altered inflammation but not survival in a lethal murine hepatitis virus-1 pneumonia model

“…Based on ICIs’ potent immunostimulatory effects, an ongoing question since the SARS-CoV-2 outbreak has been whether recent therapy with the agents worsens, improves, or has no effect on outcomes in cancer patients presenting with COVID-19. In a systematic review of 42 observational clinical studies addressing this question, we found no clear impact of prior ICI therapy on survival, severe events, or hospitalization, but the level of evidence was very low due largely to limited adjusted outcome analysis in the studies ( 1 ).…”

“…An ongoing question since the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak has been whether prior immune checkpoint inhibitor (ICI) therapy impacts outcomes in cancer patients with infection (coronavirus disease 2019, COVID-19) ( 1 ). ICIs counter the immunosuppressive effects that their targeted checkpoint molecules (e.g., PD-1 and PD-L1) exert on innate and adaptive immune responses, and they are highly effective for several cancer types ( 2 ).…”

“…ICIs counter the immunosuppressive effects that their targeted checkpoint molecules (e.g., PD-1 and PD-L1) exert on innate and adaptive immune responses, and they are highly effective for several cancer types ( 2 ). Similar ICI-induced immunostimulatory host defense effects against viral infections are being investigated ( 1 ). In COVID-19 patients, mononuclear cell PD-L1 transcript levels ( 3 ) and CD4+ T-cell surface PD-1 protein levels ( 4 ) are increased, possibly reflective of an evolving immunosuppressive response conducive to ICI therapy.…”

“…However, ICIs also induce immune-related adverse events (irAEs), including pneumonitis, and could aggravate virus-associated inflammatory injury ( 5 ). To date, observational clinical studies have provided insufficient data to determine whether ICIs impact outcomes in SARS-CoV-2-infected cancer patients ( 1 ). Therefore, since ICIs’ potent antitumor effects were first demonstrated in controlled murine experiments, we investigated the effects of ICI treatment in a murine model.…”

Programmed Cell Death Protein 1 Axis Inhibition in Viral Infections: Clinical Data and Therapeutic Opportunities

“…Those outcomes can be attributed to the underlying neoplastic process and poor performance status of the patients, the side effects of specific anti-tumor agents, or the combination of the two [ 40 ]. Consequently, it is critical to decipher the interactions between COVID-19 infection and malignancy to successfully guide clinical decisions towards the best outcome for both pathologic conditions [ 41 ]. Large cohort studies have shown that recent cytotoxic chemotherapy leads to more COVID-19-related poor outcomes [ 42 , 43 ].…”