Real-World Efficacy, Safety of Tixagevimab/Cilgavimab in Patients With Cancer After EUA Revision

As SARS-COV-2 variants continue to emerge, strategies for protecting immunocompromised patients with cancer from infection and its complications remain a priority. After tixagevimab/cilgavimab (Evusheld; AstraZeneca) received emergency use authorization (EUA) for preexposure prophylaxis (PrEP) of COVID-19, the pharmacy team at University of Southern California (USC) Norris Cancer Hospital began to administer the combination and document its distribution to evaluate its impact on infection prevention.

Although tixagevimab/cilgavimab—the first antibody therapy for COVID-19 PrEP—is no longer authorized in the United States, our single-center findings helped improve our understanding of how it and future monoclonal antibodies (mAbs) can minimize COVID-19–related complications in patients with malignancies. Study findings were presented at the Hematology/Oncology Pharmacy Association Annual Meeting, in March 2023.¹

Patients with cancer undergoing active treatment are at a higher risk of COVID-19 infection, as they are often unable to mount an adequate immune response to vaccination.^2,3 Effective COVID-19 prevention strategies are needed to circumvent poor outcomes in this vulnerable patient population.

Using the Healthcare Cost and Utilization Project National Inpatient Sample 2020 database, Abuhelwa et al conducted a retrospective cohort study and found that patients with cancer had a 21% increased risk of all-cause, in-hospital mortality and acute respiratory failure compared with those without cancer.⁴ Additionally, a meta-analysis of 38 studies demonstrated that adults with hematologic malignancy and COVID-19 infection had a 34% risk of death, with higher mortality rates (47%) among patients aged 60 years and older.⁵

The novel combination of tixagevimab/cilgavimab comprises 2 long-acting human mAbs and derives from B cells donated by convalescent patients post–SARS-CoV-2 infection. It was discovered by Vanderbilt University Medical Center before being licensed to AstraZeneca in June 2020.⁶

By binding simultaneously to 2 nonoverlapping sites on the spike protein, tixagevimab/cilgavimab effectively blocks the interaction between the virus and human angiotensin-converting enzyme 2 receptors on the host cell, thereby preventing the virus from entering.⁶ Moreover, AstraZeneca employed molecular modification techniques to optimize the pharmacokinetic profile and reduce the risk of antibody-dependent enhancement of disease by extending the half-life and decreasing Fc-mediated effector function and complement C1q binding.⁷

Results observed in the phase 3 PROVENT trial (NCT04625725) supported initial use of tixagevimab/cilgavimab to prevent COVID-19 infection in high-risk patients. Over a follow-up period with a median of 83 days, the tixagevimab/cilgavimab group demonstrated a significantly lower incidence of COVID-19 compared with the placebo group (relative risk reduction, 76.7%; 95% CI, 46.0-90.0; P < .001). There was no discernible difference in the incidence of adverse effects (AEs) between the groups, and all reported AEs were mild or moderate.³

Based on this trial, the National Comprehensive Cancer Network included tixagevimab/cilgavimab as a PrEP strategy for COVID-19 vaccination for eligible immunocompromised patients.^3,5 Despite such promising findings, only 7% of PROVENT trial participants had a history of or an active malignancy, and only 3% received immunosuppressive therapy at the time of enrollment.¹ Thus, in the context of patients with cancer and emergent variants, the applicability of PROVENT findings remained uncertain.

Because of the lack of real-world evidence for the efficacy/safety of the combination to prevent COVID-19 infection among patients with cancer, the pharmacy team at USC Norris sought to compare outcomes (between January 1, 2022, and December 31, 2022) among its adult patients with malignancies who had received B-cell-depleting agents and at least 1 dose of the antibodies and those who had not received PrEP. The control group consisted of patients with similar covariates (ie, age, sex, comorbidities, type of malignancy, type of antineoplastic therapy, COVID-19 vaccination status) at the time of PrEP administration and did not differ much in frequencies of covariates. Baseline characteristics also included labs (complete blood count with or without differential) and intravenous immunoglobulin therapy and/or anti-CD20 mAbs or Bruton tyrosine kinase inhibitors.

The primary end point was incidence of COVID-19 infection. Secondary end points included hospitalization, hospital length of stay (LOS), mortality due to COVID-19 infection, and incidence of tixagevimab/cilgavimab–related AEs. Primary outcomes were analyzed using Cox regression to generate HRs, and secondary outcomes were analyzed using logistic regression with baseline characteristics as predictors. A P value of .05 was considered statistically significant for all analyses in R.

Of the 307 patients with malignancies who received tixagevimab/cilgavimab, 89 met the inclusion criteria. Of the 16,948 patients with malignancies who did not receive tixagevimab/cilgavimab, 94 met inclusion criteria for the control group.

The mean age of participants was 66 years (range, 23-96) in the tixagevimab/cilgavimab group and 67 (range, 23-90) in the control group. In both groups, 50.6% were male and 44.3% identified as White. Most patients in both groups were diagnosed with hematological malignancies (95.1%), with non-Hodgkin lymphoma the most prevalent (61.5%). Twenty-six (14.9%) had undergone hematopoietic stem cell transplant (15 [17.6%] in the treatment group vs 11 [12.4%] in the control; P = .397) and 3 (1.6%) had received chimeric antigen receptor T-cell therapy (1 [1%] vs 2 [2%]).

Rituximab was the most frequently administered B cell-depleting agent (18 [20.2%] vs 24 [25.5%]; P = .482]) in patients given PrEP vs no PrEP, respectively. In terms of COVID-19 vaccination, 150 patients (82%) had received at least 1 dose of a vaccine regardless of manufacturer (72 [80.9%] vs 78 [83.0%]; P = .848] in PrEP vs no PrEP cohorts, respectively. A median of 3 COVID-19 vaccine doses had been administered to both groups. Furthermore, most patients (85.2%) had tested negative for COVID-19 prior to receiving tixagevimab/cilgavimab.

Results of the time-to-event analysis showed no significant reduction in the incidence of COVID-19 positivity, confirmed by either a positive SARS-CoV-2 reverse transcription–polymerase chain reaction test or patient attestation: 12 (13.5%) vs 15 (16%) patients (HR, 1.06; 95% CI, 0.49-2.29; P = .881) in PrEP vs no PrEP cohorts, respectively. Among those who tested positive for COVID-19 in both groups after PrEP administration, 0 (0%) patients in the treatment group were hospitalized compared with 5 (25%) in the control group (P = .131). When adjusted for age and COVID-19 vaccination status, tixagevimab/cilgavimab did not demonstrate a statistically significant reduction in COVID-19 positivity (HR, 0.72; 95% CI, 0.56-0.92; P = .010).

As was the case with previous clinical trial data, administration of tixagevimab/cilgavimab in this retrospective study was found to be well tolerated, with only 3 (3.4%) reports of AEs and no reports of serious cardiac events.8-10 Reported AEs included nausea, vomiting, blurry vision, and headache. Reported non–COVID-19-related deaths included 3 (3.4%) in the tixagevimab/cilgavimab group and 8 (8.5%) in the control group. There were no statistically significant differences in AEs observed between groups.

Although there was no statistically significant reduction in COVID-19 infection, tixagevimab/cilgavimab demonstrated a clinically meaningful reduction in hospitalization due to COVID-19 infection. Lack of efficacy may be due to the high mutation rates of SARS-CoV-2 and the medication’s inability to adapt to newer variants. Researchers acknowledged the limitations of this study, like its observational nature, single-center design, and relatively small sample size. Potential bias may have been introduced in the study by patient-reported outcomes (ie, COVID-19 test results) and limited knowledge of the novel mAb. Other confounding factors may have impacted results, such as differences in dosing of tixagevimab/cilgavimab between original and revised EUA (February 25, 2022) and in COVID-19 vaccination status before receiving tixagevimab/cilgavimab.

To summarize, this retrospective pre/postintervention study provides valuable insights into alternative approaches to minimize the complications of COVID-19 infection among vulnerable populations. Considering the elevated disease burden and financial strain faced by patients with cancer, it is essential that pharmacists carefully assess the value of new COVID-19 therapies for vulnerable patients. The lack of reduction in infection incidence in this study raises questions about the efficacy of PrEP strategies in immunocompromised patients with the advent of emerging variants, which led to the removal of EUA status for tixagevimab/cilgavimab as of January 26, 2023.⁸

Ongoing phase 3 trials by AstraZeneca are investigating the utility of tixagevimab/cilgavimab among immunocompromised patients in the prophylactic setting (SUPERNOVA; NCT05648110) and among nonhospitalized adults with confirmed SARS-CoV-2 infection in the treatment setting (TACKLE; NCT04723394).^9,11 SUPERNOVA addresses the challenge presented by SARS-CoV-2 variants with a new formulation of tixagevimab/cilgavimab. As of January 26, 2023, in vitro lab studies with this new formulation demonstrated neutralization of all SARS-CoV-2 variants, including variants resistant to other mAbs tested to date.¹¹ Results are expected in the latter half of 2023.

Throughout the pandemic, pharmacists have played a pivotal role in the battle against COVID-19 by advocating for and administering vaccines and antiviral medications to treat and minimize the severity of COVID-19 infection. Careful assessment of mAb therapies is another way pharmacists have demonstrated a commitment to ensuring optimal outcomes in high-risk patients.

About the Authors

Ann Tong, PharmD, is a PGY-2 oncology pharmacy resident at the University of Southern California (USC) Norris Comprehensive Cancer Center in Los Angeles, California.

Yijun Cai is a class of 2024 PharmD candidate at the USC Mann School of Pharmacy and Pharmaceutical Sciences and a pharmacy intern at the USC Norris Comprehensive Cancer Center.

Samantha Shi, PharmD, BCOP, is a pharmacy manager at the PGY2 residency director at the USC Norris Comprehensive Cancer Center.

Hien Tang, PharmD, BCOP, is a pharmacy manager at the USC Norris Comprehensive Cancer Center.

Harry Shamamian, PharmD, MBA, FACHE, is the director of pharmacy services at Norris Cancer Hospital and Clinics, Investigational Drug Service at Keck Medicine of USC.

Amir Ali, PharmD, BCOP, is a clinical pharmacist specialist and residency program coordinator at USC Norris Comprehensive Cancer Center and adjunct assistant professor of pharmacy practice at the USC Mann School of Pharmacy.

References

1. Tong A, Flores AJ, Ashouri K, et al. Real-world efficacy and safety of tixagevimab and cilgavimab (EVUSHELD) in patients with malignancies. Presented at: Hematology/Oncology Pharmacy Association Annual Conference 2023; March 29-April 1, 2023; Phoenix, AZ.

2. NCCN Clinical Practice Guidelines in Oncology. Prevention and treatment of cancer-related infections, version 3.2022. Accessed February 24, 2023. https://www.nccn.org/professionals/physician_gls/pdf/infections.pdf

3. Levin MJ, Ustianowski A, De Wit S, et al. Intramuscular AZD7442 (tixagevimab-cilgavimab) for prevention of Covid-19. N Engl J Med. 2022;386(23):2188-2200. doi:10.1056/NEJMoa2116620

4. Abuhelwa Z, Alsughayer A, Abuhelwa AY. In-hospital mortality and morbidity in cancer patients with COVID-19: a nationwide analysis from the United States. Cancers (Basel). 2022;15(1):222. doi:10.3390/cancers15010222

5. Vijenthira A, Gong IY, Fox TA, et al. Outcomes of patients with hematologic malignancies and COVID-19: a systematic review and meta-analysis of 3377 patients. Blood. 2020;136(25):2881-2892. doi:10.1182/blood.2020008824

6. Dong J, Zost SJ, Greaney AJ, et al. Genetic and structural basis for SARS-CoV-2 variant neutralization by a two-antibody cocktail. Nat Microbiol. 2021;6(10):1233-1244. doi:10.1038/s41564-021-00972-2

7. Loo YM, McTamney PM, Arends RH, et al. The SARS-CoV-2 monoclonal antibody combination, AZD7442, is protective in nonhuman primates and has an extended half-life in humans. Sci Transl Med. 2022;14(635):eabl8124. doi:10.1126/scitranslmed.abl8124

8. FDA announces Evusheld is not currently authorized for emergency use in the U.S. FDA. Accessed February 24, 2023. https://www.fda.gov/drugs/drug-safety-and-availability/fda-announces-evusheld-not-currently-authorized-emergency-use-us

9. Montgomery H, Hobbs FDR, Padilla F, et al. Efficacy and safety of intramuscular administration of tixagevimab-cilgavimab for early outpatient treatment of COVID-19 (TACKLE): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2022;10(10):985-996. doi:10.1016/S2213-2600(22)00180-1

10. Phase III double-blind, placebo-controlled study of AZD7442 for post-exposure prophylaxis of COVID-19 in adults (STORM CHASER). ClinicalTrials.gov. Updated October 25, 2022. Accessed February 25, 2023. https://clinicaltrials.gov/ct2/show/results/NCT04625972

11. Study understanding pre-exposure prophylaxis of novel antibodies (SUPERNOVA) (SUPERNOVA). ClinicalTrials.gov. Updated February 8, 2023. Accessed February 27, 2023. https://clinicaltrials.gov/ct2/show/NCT05648110