key: cord-0974281-m7tr5el1 authors: Minkove, Samuel J.; Sun, Junfeng; Li, Yan; Cui, Xizhong; Cooper, Diane; Eichacker, Peter Q.; Torabi‐Parizi, Parizad title: 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 date: 2022-04-13 journal: Rev Med Virol DOI: 10.1002/rmv.2352 sha: c9b95d0dc0c2c918b83a5b60ecb4b8e4070a7d88 doc_id: 974281 cord_uid: m7tr5el1 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. The incidence of severe disease and mortality with COVID-19 is higher in patients with cancer. [1] [2] [3] An unanswered question is whether prior immune checkpoint inhibitor (ICI) therapy, while highly effective for certain cancers, contributes to these worsened outcomes. [4] [5] [6] [7] [8] ICIs counter the immunosuppressive effects their targeted checkpoint molecules exert on innate and adaptive immune responses resulting in enhanced anti-tumour responses. 9, 10 ICIs may also affect anti-viral responses. [11] [12] [13] [14] However, the immune-related adverse events, including pneumonitis, that ICIs can produce and that occur days to months after treatment ends, could be precipitated by or complicate the intense inflammatory response COVID-19 produces in some patients. 6, 15 Determining whether prior ICI therapy has beneficial host defence or harmful inflammatory effects in cancer patients presenting with COVID-19 is critical for patient management. [4] [5] [6] [7] [8] There is an increasing number of published reports examining the impact of anti-cancer therapies, including ICIs, on outcomes for cancer patients with COVID-19. However, both cancer and non-cancer factors influence COVID-19 outcomes and confound assessment of ICI effects. [16] [17] [18] [19] While an ideal study examining the impact of ICIs on COVID-19 outcomes would adjust for these variables and a systematic review addressing this question would focus on such adjusted studies, this has generally not been the case. [20] [21] [22] [23] [24] [25] [26] [27] Among eight published systematic reviews of studies investigating cancer patients presenting with COVID-19 that previously received immunotherapies (IT) including ICIs, only 3 provided analyses of adjusted outcomes with IT, and each of these was based on five or fewer published studies. [20] [21] [22] [23] [24] [25] [26] [27] Furthermore, only two of these systematic reviews specifically differentiated between ICIs and non-ICI ITs. 26, 27 This distinction is essential since ICIs have different mechanisms of action and biologic effects than non-ICI ITs and in two recent studies, <10% of patients reportedly receiving ITs had received ICIs. 28, 29 Of note, despite the rapidly increasing number of reports providing data on prior ICI treatment in cancer patients presenting with COVID-19, the two systematic reviews available so far examining this question included only 10 and 13 published reports respectively. 26, 27 Therefore, the primary purpose of our systematic review was to analyse studies presenting the adjusted effects specifically of ICI therapy on either survival, a severe event, or need for hospitalisation in cancer patients presenting with COVID-19. This systematic review was prepared using the Preferred Reporting Published studies were retrieved and analysed that provided data on patients with cancer presenting with COVID-19 and that allowed a within study comparison of patients that had previously received ICI therapy (ICI patients) versus those who had not (non-ICI patients) regarding survival, severe events, or need for hospitalisation related to COVID-19. Severe events included either a composite severe event (i.e., any one of several outcomes such as respiratory failure, sepsis, or intensive care unit (ICU) admission defined and reported together as a severe event), development of respiratory failure (including Acute Respiratory Distress Syndrome or need for intubation/mechanical ventilation or non-mechanical ventilatory support), non-pulmonary organ failure or sepsis, or need for ICU admission. Using search terms and strategies listed in Supplementary-File B published studies were identified in the following databases from inception through 5/1/21 without language restrictions: PubMed, EMBASE, Scopus, and Web of Science. Title and abstract followed by full text reviews were conducted by two authors (S.J.M. and P.Q.E.) and disagreements resolved by a third author (P.T.P.). Recovered reports were hand searched for additional studies. Studies were included only when it could be confirmed from the publication or by correspondence with study authors, what the number and outcomes were of patients that had received ICI therapy as opposed to other ITs. Abstracts were not included. Two investigators (S.J.M. and P.Q.E.) independently extracted data from reports using a standardised extraction form (Supplementary-File C). These data, detailed fully in the Supplemental-Methods, included among others: numbers of patients that had or had not 2 of 14previously received an ICI agent; whether ICIs had been administered alone or with another anti-cancer therapy; time from last ICI treatment to COVID-19 diagnosis; patient outcomes comparing ICI versus non-ICI patients including mortality, severe events and need for hospitalisation; duration and completeness of follow-up (i.e., proportion of patients follow-up was available for); whether a study's patient enrolment potentially overlapped with another study; and the methods (model and effect type and variables adjusted for) and results of adjusted analyses performed for the effects of ICI on the outcomes of interest. If more than one type of severe event type was reported in a study, only one was selected for analysis in the following hierarchical order; a composite severe event, development of respiratory failure, non-pulmonary organ failure or sepsis, or need for ICU admission. When sufficient individual patient data were available in reports for adjusted analysis, these were recorded. Two authors (S.J.M and P.Q.E) independently assessed included studies for quality of evidence using the nine-point Newcastle-Ottawa Scale tool (Supplementary-File D). 30 Disagreements were resolved by a third author (P.T.P.). GRADE analysis was performed to assess certainty of data. 31 Publication bias was assessed by funnel plot and Egger's regression. Results from multivariable analyses were used when presented. Hazard ratio (HR) and relative risk (RR) were converted to odds ratio (95% CIs) (OR) (proportional hazard was assumed for HR). If multivariable analysis was not reported but individual patient data were provided, we performed multivariable logistic regression with these data if they included at least 10 subjects with the less frequent outcome and allowed adjustment for all of the following: age, gender and the presence or absence of hypertension (HTN), diabetes (DM), heart disease and chronic obstructive pulmonary disease (COPD). In one study that reported results from multivariable analyses for both ICI alone and ICI plus another anti-cancer agent, the results were combined for a single analysis. 32 These subgroup analyses were based on the following rationales: small studies are inherently at risk for imprecision and prior systematic reviews have excluded studies with <10 patients receiving IT; patients requiring ICIs with other anti-cancer therapies might have advanced cancer and worsened outcomes; more recent versus more remote exposure to ICIs might affect the risk of immunerelated adverse events; patients included repetitively in more than one study might influence analysed outcomes; risk of bias and study quality might impact study results. Studies not reporting data for these subgroups were not included in the respective sensitivity analysis. We used SAS version 9.4 for the multivariable analysis of individual patient data. Meta-analyses were conducted using R Table 1 summarises study characteristics including country, centre number, cancer type, COVID-19 diagnosis-method, patient location, data source and enrolment dates. Total length of follow-up ranged from 12 to 218d in studies, but follow-up duration and completeness were unclear in 18 studies. All studies were observational, 34 were solely retrospective, and 4 included retrospective and prospective patients. Seven studies provided adjusted results for one or more outcome and two studies provided sufficient individual patient data for adjusted analyses. Only four studies specifically focussed on prior ICI therapy alone and two of these reported adjusted outcomes. of ICI versus non-ICI patients. All 9 studies that provided adjusted outcomes or individual patient data for adjusted analysis had scores ≥7. Scores <7 in studies were due to both inadequate comparability of study groups and unclear or insufficient follow up. Thirty-eight studies provided data allowing comparison of mortality in ICI versus non-ICI patients (Figure 1 , Supplementary- Characteristics from individual studies employed in four of the five sensitivity analyses are shown in Supplementary- Table 3 . Data on the Newcastle Ottawa score is noted above. As shown in Table 3 Twenty-four studies provided data comparing severe events in ICI Sensitivity analyses were performed on the same subgroups as for mortality (Table 3, Supplementary-Table 3 ). In studies with possible overlapping patent enrolments, the OR of severe events was increased (p = 0.02) in ICI patients. Study subgroups did not differ significantly in the remaining four sensitivity analyses (p = 0.33-0.83). Fifteen studies provided data comparing need for hospitalisation in ICI versus non-ICI patients (Figure 2 , Supplementary- Table 2 ). Only Table 3 , Table 3 ). Because all studies analysed here were observational and most were retrospective, the overall certainty of evidence presented starts at a low level. 75 Certainty of evidence was further downgraded to very low, based on risk of bias, inconsistency, indirectness, and/or imprecision, for four of the five GRADE criteria for each of the three outcomes assessed (Supplementary- Table 5 ). [20] [21] [22] [23] [24] [25] [26] [27] Unfortunately, GRADE analysis demonstrated that even with this increasing body of data the certainty of evidence regarding the effects of ICIs in cancer patients with COVID-19 is very low. The literature has repeatedly emphasised the need to determine whether prior ICI therapy impacts outcomes in cancer patients with COVID-19. [4] [5] [6] [7] [8] When treating patients with COVID-19 pneumonia, any theoretical anti-viral effect that ICIs exert must be weighed against the well documented immune-related adverse events, including pneumonitis, that ICIs can produce. 6, [11] [12] [13] [14] [15] There is growing concern of probable synergy, or an inability to distinguish between COVID-19 pneumonitis and pneumonitis as an adverse event ICI therapy. 76 Additionally, as a result of reinvigorated Tcells, patients on ICIs might have an increased risk of cytokine F I G U R E 2 Forrest plots showing the effect of prior immune checkpoint inhibitor (ICI) therapy on the odds ratio [OR (95% CI)] of severe events and need for hospitalisation in studies providing data on cancer patients presenting with COVID-19 that had or had not previously received ICIs. Also shown for each outcome are the total numbers of patients (Total) and the number of patients with either event (NE) that had or not previously received ICI. For severe events, shown at the top are the adjusted effects of ICIs on the OR of a severe event in five the studies reporting these data and the combined adjusted OR and I 2 value (random effects model). See Table 2 for the models, variables and effect types reported in these studies. Effects were converted to the OR of a severe event for all studies as described in the methods. Shown at the bottom are the unadjusted effects of ICIs on the OR of a severe event from 19 studies that provided data allowing this calculation and the combined OR and I 2 value. The effects of ICIs did not differ significantly (p = 0.96) comparing studies with adjusted and unadjusted results and the overall OR and I 2 value of a severe event for all 24 studies is shown at the very bottom of the panel. For hospitalisation, only 2 studies reported the adjusted effects of ICIs on the need for this and no combined OR was calculated for these two. Thirteen studies provided unadjusted OR for hospitalisation and the combined OR and I 2 value for these studies are shown. The adjusted effects of ICs in the two studies did not differ significantly (p = 0.25) from the unadjusted effects from the 13 studies that allowed this calculation and the overall effect of ICIs on the OR (95%CI) and I 2 value of hospitalisation for all 15 studies is shown at the very bottom of the panel release syndrome, an important cause of mortality in COVID- 19. 77 If harmful, besides implications for discontinuation of ICI therapy, this determination would influence the management of worsening organ injury in infected patients, such as possibly supporting earlier corticosteroid use for pneumonitis. 78 Alternatively, if ICIs exert a beneficial host defence effect as proposed for other viral infections, continued or even initiation of ICIs might be considered. [11] [12] [13] [14] The present study highlights the weaknesses in currently available data to assess the impact of ICI therapy on COVID-19 outcomes. Thirty-eight of the studies analysed were solely or partially retrospective ones. Only four studies specifically examined the effects of ICIs on the outcomes of cancer patients with COVID-19. Only one study included more than 100 ICI patients and 26 (62%) had <10 patients. Despite the complexity of cancer patients with COVID-19, eight of the nine studies providing adjusted outcome data controlled for seven or fewer variables. There were not sufficient data to examine the effects of specific ICI regimens. While sensitivity analysis suggested some associations with timing of ICI treatment, treatment regimen, and studies with potential overlapping patient enrolment, these findings were not consistent across all three outcomes and are difficult to interpret. Overall, the present analysis indicates that more comprehensive observational studies will be required to determine how ICIs impact COVID-19 outcomes in cancer patients. Such databases would need to contain detailed patient-level data and clearly differentiate ICI from non-ICI IT-treated patients. The databases would have to reliably assess the impact of a range of covariates confounding interpretation of the effects of ICIs including among others: type and stage of cancer, presence of other anti-cancer therapies, and patient performance status; the certainty, duration and severity of COVID-19 itself; the specific type, mechanism of action, and regimen of the ICIs being used; information on a range of non-cancer variables like those in the Charlson co-morbidity index 79 ; and comprehensive assessment of outcomes and patient follow-up. Power analysis, possibly based on the known ICI adverse event rate in uninfected cancer patients, would be necessary. There are growing databases and registries that could provide stronger estimates of the effects of prior ICI therapy in cancer patients with COVID-19. Both national and international registries focussed primarily on cancer patients such as The Thoracic Cancers International COVID-19 Collaboration might provide the most informative results. 80 More general registries like the US Veterans Administration's National Database could also be used. 81 Early data from several of these sources were included in the present analysis. 29, 32, 42, 44, 46, 48, 52, 54, 61 On the one hand, the persistence of SARS-CoV-2 variants and continued high infection rates coupled with the widespread use of ICIs for cancer emphasises the importance of understanding how prior ICI treatment alters COVID-19 outcomes in cancer patients. But these circumstances may provide a unique opportunity to understand whether ICIs should be considered for the treatment of other types of acute or chronic infections. Therapy with ICIs has been proposed for infections as varied as malaria, HIV and HBV. 82 While several trials directly assessing the effects ICIs in COVID-19 have been planned (NCT04413838, NCT04356508, NCT04268537, NCT04268537, NCT04333914), results are not available. But a comprehensive assessment of the effects of ICI therapy in COVID-19 cancer patients might prove informative regarding their therapeutic value for this and other types of viral infection. There are several limitations to this study. First, although our search criteria were broad and resulted in over 20,000 reports, in this rapidly evolving field it is possible that very recent studies were overlooked. Second, our search did not include pre-print literature which had not yet undergone peer-review. Third we restricted our review to English publications. Finally, despite attempts to contact authors to clarify patient numbers, outcomes and types of IT therapy investigated, 13 studies had to be excluded from analysis as there was no response to these communications. In conclusion, while vaccination has reduced COVID-19 in some counties, the infection remains a pressing health problem in large parts of the world. Even with more widespread vaccination, SARS-CoV-2 and its variants will remain a health threat well into the future, especially for patients with cancer. Given the effectiveness and need for ICI therapy in many cancer patients, it is essential to understand with the most credible evidence how ICIs impact outcome when these patients develop COVID-19. 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Additional supporting information can be found online in the Supporting Information section at the end of this article.