Patients with cancer who contract COVID-19 are more vulnerable than the general population at every stage of the COVID-19 continuum: from contagion exposure to breakthrough COVID-19 after vaccination, hospitalization, critical illness, prolonged morbidity (Post-Acute Sequelae of COVID [PASC]/“long-COVID”) and death3, 4, 10. Kuderer et al.1 previously studied a cohort of 900 clinically and demographically diverse patients with cancer from the COVID-19 and Cancer Consortium (CCC19) registry. Several cancer-specific (worse ECOG status and active malignancy) and non-cancer-specific (male sex, older age, positive smoking history, number of comorbidities, and receiving hydroxychloroquine and azithromycin) parameters were associated with increased 30-day all-cause mortality.
Many non-cancer-specific features (e.g., older age) are more common among individuals with cancer. Moreover, people with cancer may experience immune suppression from the state of malignancy itself or medication-related such as antineoplastic therapy and steroids1, 14, leading to a decreased humoral response to vaccination15, 16, increased risk for breakthrough infection4, 17, 18, and worse overall clinical outcomes from COVID-1919. Patients with cancer also have more frequent and prolonged healthcare interactions compared to their peers without chronic or disabling illness, due to the extended temporal nature of antineoplastic treatment and follow-up with multiple providers, often across more than one healthcare settings, leading to increased risk of SARS-CoV-2 transmission3.
Importantly, COVID-19 complicates cancer care by limiting screening, diagnosis, and timely treatment options, potentially facilitating disease progression and significant psychological distress3, 20. For the above reasons, patients with cancer are a high-risk group that could benefit significantly from the timely initiation of effective treatment against SARS-CoV-2.
Monoclonal antibodies (mAbs) that block SARS-CoV-2 entry into host cells by binding to the viral spike glycoprotein have proven to be excellent outpatient therapeutic agents in clinical trials and quasi-experimental studies, when used against susceptible strains5, 21, 22. Since November 2020, six anti-SARS-CoV-2 mAbs (bamlanivimab, bamlanivimab/etesevimab, casirivimab/imdevimab, sotrovimab, bebtelovimab, and tixagevimab/cilgavimab [for primary prophylaxis]) – have received EUA, with only the last option still available, as the rest do not have activity against circulating Omicron variants any longer12, 23.
There is a relative paucity of data on the protective efficacy of mAbs specifically for patients with cancer10. In the phase 3 portion of the BLAZE-1 clinical trial that supported efficacy of bamlanivimab/etesevimab for patients with mild or moderate COVID-195, patients with cancer were classified with other patients who have impaired immune system (e.g., solid organ transplant recipients), under the broad inclusion criterion of being immunocompromised, despite substantial, clinically-relevant variations in depth and types of immunosuppression. Similarly, Ganesh et al., in a study of more than 3,500 patients who received bamlanivimab or casirivimab/imdevimab, referred broadly to immunocompromised status, which is one of the inclusion criteria under the EUA8. In a retrospective cohort study by Jalbert et al.9 that included more than 13,000 patients who received casirivimab/imdevimab, patients with cancer or chemotherapy were included as a separate category for cohort-matching purposes, but their malignancy characteristics were not described, nor the direct effect of mAbs on this subpopulation. And in the COMET-ICE randomized clinical trial for sotrovimab, patients with cancer receiving immunosuppressive chemotherapy or immunotherapy were explicitly excluded7.
To the best of our knowledge, our study is the first to assess the efficacy of mAbs exclusively in COVID-19 patients with both solid and hematologic malignancies, compared to appropriate controls who did not receive mAbs or any other outpatient treatment, while adjusting for possible confounders. We observed a significant, sustained reduction in hospitalization rates and peak O2 requirements among sixty-three patients with cancer who received mAbs as outpatients, compared to eighty-nine who did not (Table 3, Figures 3 & 4). Additionally, patients with cancer and COVID-19 treated with mAbs had longer 90-day survival, compared to those who did not (Table 3, Figure 2). To our knowledge, such a mortality benefit from mAbs, compared to untreated patients, has not been previously shown in a cohort of patients with solid tumors and HM. Our findings agree with several other multicenter observational series of immunocompromised patients with mild or moderate COVID-19, who were given mAbs in the outpatient setting, which demonstrated lower than expected hospitalization and mortality rates9, 22, 24. Similarly, our results agree with the findings of a Czech multicenter study that included only patients with HM who received bamlanivimab or casirivimab/imdevimab25. In that cohort, the investigators found lower rate of progression to severe disease among patients with HM who received mAb compared to those who did not, and a borderline mortality benefit in the remdesivir/convalescent plasma “naïve” subgroup25.
Another important finding from our study was that vaccinated patients, especially those who had received ≥3 doses of an mRNA vaccine, had lower mortality rates (Figure 4), despite concerns for lower immunological vaccine efficacy among immunocompromised patients15, 16, and one small study from the CCC19 registry, which showed comparable clinical outcomes between unvaccinated patients with cancer and those who had received 2 doses of an mRNA vaccine18. The results of the present report are consistent with those of a previously published study at our center among organ transplant recipients26, and the updated CCC19 data17, highlighting that vaccination of immunocompromised patients, especially with additional “booster” doses, is an essential preventive strategy against severe COVID-19 and death.
Our study has limitations: First, data were retrospectively collected, but all outcome variables were clearly defined and easy to extract from the electronic medical record (EMR). Second, the single-center design may limit the generalizability of results. However, our findings are comparable with those from several larger multi-center studies and in agreement with the well-established benefits of mAbs in the general population. Third, whether an eligible patient receives mAbs is multifactorial and dependent on clinical judgement. ECOG status could play a role in these decisions, and we did not have enough entries to include it in our multivariable models. Fourth, the groups (mAbs vs. controls) were relatively small, and we did not perform propensity-score matching. Nonetheless, the treatment and non-mAbs groups had overall well-balanced baseline characteristics (Table 1) and the difference in clinical outcomes was significant even after appropriate multivariable adjustments.
Last, our findings no longer apply to circulating variants: Most patients in our study contracted SARS-CoV-2 during the peak of the Delta wave and at the beginning of the Omicron (BA.1 variant) wave; the majority of patients received bamlanivimab/etesevimab or casirivimab/imdevimab. In January 2022, the FDA limited the use of bamlanivimab/etesevimab and casirivimab/imdevimab for only non-Omicron variants12. After January 2022, >95% of SARS-CoV-2 infections in Rhode Island were caused by the Omicron variant, therefore these mAbs were no longer being administered in our State, reflecting the trend in the Northeastern US27. Likewise, the EUA for sotrovimab was retracted in April 2022, when the BA.2 Omicron sub-variant became dominant12. Bebtelovimab, which had EUA since February 2022 and was still active against most circulating Omicron variants, was underrepresented in our study, as only 1 patient received it. And in December 2022, the FDA revoked the EUA authorization for the last available COVID-19 monoclonal antibody treatment, bebtelovimab, as well. This was mainly justified by the lack of activity against Omicron subvariants BQ.1 and BQ.1.1, which at the time of this manuscript represent >60% of SARS-CoV-2 infections nationally23.
Thus, mAbs lost their clinical utility rather fast, as the result of spike protein mutations28 An equally effective oral antiviral against SARS-CoV-2, nirmatrelvir/ritonavir (Paxlovid®), has maintained its efficacy against all Omicron sub-variants28, and became the mainstay of outpatient (mild to moderate) COVID-19 treatment for many patients. Notwithstanding, ritonavir is a potent CYP inhibitor, and clinically relevant drug-drug interactions29 make its administration often challenging for patients on multiple medications, such as those with cancer.
In conclusion, we found that the administration of mAbs to non-hospitalized patients with cancer was associated with markedly decreased morbidity and mortality, compared to eligible for mAbs but untreated controls, after adjustment for possible confounders. Despite the wide availability of Paxlovid®, and based on the results of this study, we believe there is still an important role for passive immunization, e.g. high-titer convalescent plasma that has EUA for treatment of COVID-19 in immunosuppressed patients30, 31. Moreover, the development of novel mAbs against emerging SARS-CoV-2 variants should be a research priority.
According to a recent position statement10, investigations and policies regarding ongoing or future pandemics should: (1) include patients with cancer in all treatment clinical trials, (2) collect specific data on cancer characteristics and treatment, and (3) include malignancy factors as covariates or as strata for subgroup analyses. We strongly support these suggestions, in addition to educating patients with cancer about treatments for COVID-19 that are available to them, to ensure timely access. Although cancer necessitates a close relationship between patients and health care providers that may facilitate iatrogenic exposure to COVID-19, with host and treatment factors predisposing to severe illness, the field of oncology also offers the opportunity for close, careful management in the setting of preexisting strong patient-provider alliances.