Oral antivirals for COVID-19 among patients with cancer

Purpose: Immunocompromised individuals, such as those diagnosed with cancer, are at a significantly higher risk for severe illness and mortality when infected with SARS-CoV-2 (COVID-19) than the general population. Two oral antiviral treatments are approved for COVID-19: Paxlovid® (nirmatrelvir/ritonavir) and Lagevrio® (molnupiravir). There is a paucity of data regarding the benefit from these antivirals among immunocompromised patients with cancer, and recent studies have questioned their efficacy among vaccinated patients, even those with risk factors for severe COVID-19. Methods: We evaluated the efficacy and safety of nirmatrelvir/ritonavir and molnupiravir in preventing severe illness and death using our database of 457 patients with cancer and COVID-19 from Brown University-affiliated hospitals. 67 patients received nirmatrelvir/ritonavir or molnupiravir and were compared to 56 concurrent controls who received no antiviral treatment despite being eligible to receive it. Results: Administration of nirmatrelvir/ritonavir or molnupiravir was associated with improved survival and lower 90-day all-cause and COVID-19-attributed mortality (p<0.05) and with lower peak O2 requirements (ordinal odds ratio [OR] 1.52, 95% confidence interval [CI] 0.92–2.56). Conclusion: Acknowledging the small size of our sample as a limitation, we concluded that early antiviral treatment might be beneficial to immunocompromised individuals, particularly those with cancer, when infected with SARS-CoV-2. Larger-scale, well-stratified studies are needed in this patient population.


Introduction
Patients with cancer represent a diverse group, most of whom are at an elevated risk of severe illness and mortality when infected with SARS-CoV-2 [1].They often exhibit additional risk factors for severe COVID-19, including older age, increased number of comorbidities, immunosuppressive therapies, metastatic disease, and frequent healthcare interactions [1].Moreover, individuals with cancer, particularly hematologic malignancies (HMs), tend to mount weaker immune responses to COVID-19 vaccines than those without cancer [2,3].
Both nirmatrelvir/ritonavir (Paxlovid®) and molnupiravir (Lagevrio®) are FDA-approved for the treatment of COVID-19 based on the results of two randomized clinical trials (RCTs) from previous phases of the pandemic [4,5], with the latter being under emergency use authorization.Additionally, their effectiveness was con rmed in large retrospective registries, which included small proportions of immunosuppressed patients [6,7].That being said, several groups [4,5,[8][9][10][11] have studied the bene cial role of those antivirals among eligible immunocompromised outpatients only, with relatively mixed results.A post hoc analysis from the aforementioned RCT [5] showed that molnupiravir treatment of mild-to-moderate COVID-19 in non-hospitalized, unvaccinated, immunocompromised adults was safe, but the clinical bene t from its administration, although numerically substantial, did not reach statistical signi cance [8,11].Importantly, adverse effects due to drug-drug interactions (DDI) between medications that immunocompromised patients may already be taking, and nirmatrelvir/ritonavir may impact its tolerability among patients with cancer [12][13][14].Moreover, recently completed RCTs of both drugs showed a lack of clinical bene t from their use among low-risk patients or even vaccinated high-risk patients in the current era of Omicron variants and widespread immunity to SARS-CoV-2 [15][16][17][18] To our knowledge, no studies to date have speci cally appraised the effectiveness of molnupiravir and nirmatrelvir/ritonavir in preventing hospitalization and mortality, exclusively among patients with solid or hematologic malignancies, using appropriate, concurrent controls.In this study, we conducted a retrospective analysis utilizing patient-level data from our comprehensive institutional registry.We aimed to compare clinical outcomes between outpatients with cancer and COVID-19 who took molnupiravir or nirmatrelvir/ritonavir and concurrent controls, that is, patients with cancer who were diagnosed with COVID-19 and did not receive any antiviral treatment, although they were eligible for it.

Study design
We conducted a retrospective study at hospitals a liated with Brown University.Our institutional database included all patients with active or historical malignancies diagnosed with COVID-19 between April 1, 2020, and August 1, 2023.Patients were excluded from the study if they met any of the following criteria: (1) they received anti-spike monoclonal antibodies (mAbs), the e cacy of which was shown in our previous study [19], (2) they had elevated oxygen requirements due to COVID-19 compared to their baseline needs, (3) they had COVID-19 before EUAs for molnupiravir or nirmatrelvir/ritonavir were issued (December 22, 2021), or (4) they were treated with both oral antivirals (Fig. 1).This study was approved by the Lifespan Institutional Review Board.

Statistical analyses
Continuous variables are presented as medians with interquartile ranges (IQRs), while nominal and ordinal variables are shown as numbers with percentages.To compare differences between the two groups, we used the chi-square test or Fisher's exact test as appropriate.We assessed 90-day survival using Kaplan-Meier curves, and differences between groups were tested with the log-rank test.To examine the relationship between molnupiravir administration, nirmatrelvir/ritonavir administration, and peak oxygen (O 2 ) requirements, we used ordinal logistic regression analysis.We considered statistical signi cance at a two-tailed p value of 0.05.

Baseline demographic and clinical characteristics
During the study period, 457 patients with cancer and SARS-CoV-2 infection were identi ed.Of the 389 (85%) patients who did not receive oral antivirals, 234 (51%) were excluded because they had COVID-19 prior to the availability of oral antivirals, 103 (23%) were excluded because they received mAbs, and 7 (2%) patients were further excluded due to increased O 2 requirements at presentation.Thus, the control group consisted of 45 patients who (a) had not received molnupiravir, nirmatrelvir/ritonavir, or mAbs but were eligible for antiviral treatments since they (b) had SARS-CoV-2 infection after December 22, 2021 (post-EUA for nirmatrelvir/ritonavir), (c) did not have increased O 2 requirements at presentation, and (d) were not admitted to the hospital for COVID-19.56 patients received nirmatrelvir/ritonavir alone, and 11 patients received molnupiravir alone.Ten patients were excluded from the nirmatrelvir/ritonavir treatment group due to the administration of mAbs (8 such patients), molnupiravir (1 such patient), or both (1 such patient).Three patients were excluded from the molnupiravir treatment group due to the administration of mAbs (2 such patients), nirmatrelvir/ritonavir (1 such patient), or both (1 such patient).
The baseline demographic and clinical characteristics of these three groups were largely comparable (Table 1).51% (57/112) of patients identi ed as male, although only 18% (2/11) of those in the molnupiravir group were male, and male gender was associated with higher mortality overall (Suppl.Table 1).48% (54/112) of the patients were current or former smokers, and the most common comorbidity was hypertension (56%, 63/112).Most patients contracted COVID-19 in 2022 and 2023.There were no signi cant differences in vaccination status or the number of doses between groups.a Total will be greater than the total number of patients due to row overlap.
Table 2 provides an overview of the distribution of cancer characteristics within all three groups.Most patients had solid tumors (70%, 78/112).Patients who received nirmatrelvir/ritonavir were more likely than their counterparts to have prostate cancer (controls: 2%, molnupiravir: 9%, nirmatrelvir/ritonavir: 14%).ECOG scores were not reported for 17 patients (8 controls, 8 who received nirmatrelvir/ritonavir and 1 who received molnupiravir).Patients who received nirmatrelvir/ritonavir were less likely than controls to have an ECOG score ≥2.We did not observe a clear association between ECOG scores and mortality (Suppl.Table 2).The most common anticancer treatment among patients who received nirmatrelvir/ritonavir was locoregional therapy (64%, 36/56), while cytotoxic therapy was most common for both the molnupiravir (91%, 10/11) and control (60%, 27/45) groups.ECOG Eastern cooperative oncology group, NSCLC Non-small cell lung cancer, SCLC small cell lung cancer.
a Total will be greater than the total number of patients due to row overlap.

Discussion
To our knowledge, no studies have assessed the e cacy of nirmatrelvir/ritonavir and molnupiravir speci cally among patients with cancer and COVID-19 to date.Although we cannot entirely rule out confounding from imbalances in baseline ECOG scores and male sex (for molnupiravir), we provide herein real-world evidence, using objective outcomes and appropriate controls, of potential clinical bene ts from early administration of anti-SARS-CoV-2 oral antiviral medications in this vulnerable and growing patient population.
In addition to the seminal randomized controlled trial [4], two additional recent observational but large studies from China [20] and British Columbia [21] showed bene t from the administration of nirmatrelvir/ritonavir, especially among immunocompromised patients, in agreement with our results.However, vaccination coverage in the rst two studies was remarkably low: unvaccinated [4] and 26.5% vaccinated [20], compared to our report (at least 3 doses of an mRNA vaccine in > 50% of patients in all groups, Table 1).Nevertheless, the study by Dormuth et al. [21] was performed in a highly vaccinated patient population (> 50% had 3 doses with approximately 30% 4 or more).That study showed incremental bene t from Paxlovid® treatment in severely > moderately immunosuppressed individuals but no statistically signi cant bene t among non-immunosuppressed but otherwise high-risk patients with COVID-19.Deeply immunocompromised patients, especially those with hematologic malignancies, are at high risk for both severe COVID-19 [22] and poor response to vaccination [23,24].Our ndings and those of the above studies indicate that such patients could bene t the most from nirmatrelvir/ritonavir and highlight the importance of risk strati cation in the study of antiviral treatments among patients broadly considered "immunosuppressed".Furthermore, the heterogeneity of patients referred to as "highrisk" for severe COVID-19 dictates caution in interpreting the recent results from randomized controlled trials showing no bene t from antiviral medications among vaccinated patients under that broad term [15,17,18].
It should be noted that DDIs between medications that oncologic patients often take and Paxlovid® may signi cantly affect the risk-bene t ratio or even be prohibitive of its administration [12][13][14].Nirmatrelvir, an antiviral protease inhibitor against SARS-CoV-2, is pharmacokinetically enhanced by ritonavir, a potent CYP3A4 inhibitor, to achieve therapeutic plasma concentrations [25].This enhancement becomes critical when considering co-administration with tyrosine kinase inhibitors (TKIs), which are widely utilized in the targeted treatment of various malignancies, such as leukemia, non-small cell lung cancer (NSLC), and certain breast cancers, due to their primary metabolism via CYP3A4 [13].Beyond TKIs, other commonly used chemotherapeutics, such as taxanes and vinca alkaloids, also share this metabolic pathway, heightening the risk of cumulative toxicity [26,27].The concomitant use of Paxlovid® in patients with cancer, who might already exhibit elevated levels of chemotherapeutic agents due to the multifaceted impact of COVID-19 on drug metabolism and clearance, further complicates the therapeutic landscape [28].These complexities underscore the need for a thorough evaluation of potential DDIs when using Paxlovid®, as well as careful monitoring and adjustment of chemotherapeutic dosing, to minimize the risk of enhanced toxicity while effectively managing both cancer and COVID-19.
The RCT data supporting the e cacy of Lagevrio® among unvaccinated patients were weaker than those of Paxlovid®, and its EUA was supported by a marginal vote.A recent registry-based study claimed a signi cant bene t, almost similar to Paxlovid®, especially among elderly patients, even after adjustment for vaccination status and time from last vaccine dose [7].Nevertheless, the PANORAMIC clinical trial [29], where > 96% of patients were fully vaccinated, showed no difference in clinical outcomes between molnupiravir and usual care alone, similar to the results of a recent systematic review and metaanalysis [16].
Despite hesitancy due to con icting data, molnupiravir has gained some acceptance as an easily available, DDI-free oral treatment against COVID-19 in immunosuppressed patients taking multiple medications that could interact with ritonavir [4,5,[8][9][10][11].Again, the results are rather mixed: among 55 immunocompromised participants in a post hoc analysis from the MOVE-OUT trial, molnupiravir treatment demonstrated a noteworthy reduction in hospitalizations or deaths (8.3% vs. 22.6% for placebo) and a lower incidence of adverse events (25.0% vs. 45.2% for placebo) by day 29.However, none of these results were statistically signi cant [8,11].In another retrospective study of diverse immunocompromised US Veterans, > 50% of whom had received a vaccine booster, oral antiviral treatment was associated with a signi cant reduction in the composite outcome of hospitalization or death, largely driven by a decreased 30-day mortality rate.Of note, the investigators found similar magnitudes of bene t for molnupiravir and nirmatrelvir/ritonavir [30].However, among lung transplant recipients, neither vaccination nor antiviral treatment with either remdesivir or molnupiravir had a signi cant effect on the odds of severe COVID-19, highlighting once again the importance of risk strati cation within the "immunocompromised" patient population, with implications for decreased treatment bene ts among the most immunosuppressed, especially those with concomitant structural lung disease [31].To our knowledge, there are no published data on molnupiravir e cacy speci c to the oncologic patient population.Although our sample size was too small to draw rm conclusions, no deaths occurred in the molnupiravir group.Our ndings and the overall consensus that early antiviral treatment may be bene cial potentially support its use in selected patients when DDIs prohibit the administration of Paxlovid®.
Our study has several limitations.First, it was a single-center, retrospective study with a relatively small number of patients, although it was comparable to those of other similar reports [8][9][10]20].However, we used objective outcomes, which can be reliably abstracted from Electronic Medical Records (EMR).
Utilizing concurrent controls and ensuring eligibility for treatment strengthens the study by preventing bias stemming from varying base mortality rates at different phases of the pandemic (an important caveat when using "historical controls" [32]) and by addressing potential confounding due to indication, respectively.Second, imbalances in ECOG scores and male sex could have in uenced the outcome; however, the latter only applied to the small number of patients treated with molnupiravir.Furthermore, we analyzed COVID-19 attributable mortality to limit potential biases from cancer prognosis.Third, the number was too small to allow not only multivariable adjustments but also key subgroup analyses (e.g., among patients treated with rituximab or other anti-B-lymphocyte monoclonal antibodies), which should be the focus of future studies.
In conclusion, we found a signal for bene t from treatment of COVID-19 with an oral antiviral, especially nirmatrelvir/ritonavir, among patients with cancer.Importantly, our report and review of the literature highlight the need for larger samples and rigorous strati cation of "high-risk" patients in observational studies and randomized controlled trials of anti-COVID-19 treatments.

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