COVID-19 may have caught the world off guard in 2020, but in the 2 years since the pandemic began, several effective monoclonal antibodies and antiviral drugs have emerged to protect the most vulnerable patients.
The ASCO Post spoke with Gunjan L. Shah, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center, and Michael Boeckh, MD, PhD, Professor and Head of the Infectious Disease Sciences Program of the Vaccine and Infectious Disease Division at Fred Hutchinson Cancer Research Center, about the evolving armamentarium used to treat patients with cancer who are immunocompromised and/or undergoing transplantation. Currently, all available agents are under emergency use authorization (EUA) from the U.S. Food and Drug Administration.
Gunjan L. Shah, MD
Michael Boeckh, MD, PhD
Preexposure Prophylaxis: Tixagevimab/Cilgavimab
A combination of two long-acting monoclonal antibodies—tixagevimab and cilgavimab—is available in the preexposure prophylaxis setting. Tixagevimab/cilgavimab is administered by intramuscular injection and is believed to cover the omicron variant based on in vitro evidence.
“For preexposure prophylaxis, patients must be older than age 12, weigh at least 40 kg, and should not actively have COVID-19,” said Dr. Shah. “We are using this combination in patients with hematologic malignancies who have either not responded to COVID-19 vaccination or have reasons why we expect they will not mount a response to vaccination, such as having received a hematopoietic cell transplant or [chimeric antigen receptor] (CAR) T-cell therapy recently or treatment with B-cell–depleting or other immunosuppressive therapies.”
Although monoclonal antibodies are generally well tolerated, the main side effects to watch for are infusion reactions, which mostly occur within the first 24 hours. For tixagevimab/cilgavimab, the EUA includes a caution for cardiovascular events, said Dr. Shah, as some patients who received the drug had a myocardial infarction or cardiac failure—a small number but a greater incidence than seen in placebo recipients.
“The level of evidence for the agents under EUA is high, with the majority having randomized trials supporting their use,” Dr. Shah said. “The randomized phase III PROVENT trial [ClinicalTrials.gov identifier NCT04625725] showed that tixagevimab/cilgavimab prevented the development of COVID-19 prior to the Omicron variant.” [Editor’s Note: The U.S. Food and Drug Administration recently approved a higher dose of tixagevimab/cilgavimab, because available data indicate that a higher dose may be more likely to prevent infection by the Omicron subvariants BA.1 and BA.1.1 than the originally authorized dose.]
In addition to tixagevimab/cilgavimab, Dr. Boeckh and colleagues are studying the monoclonal antibody sotrovimab as upfront prophylaxis in an ongoing clinical trial of high-risk allogeneic transplant recipients.
“If proven effective, sotrovimab would be another good option to give prophylactically,” said Dr. Boeckh. “The in vitro evidence for sotrovimab for the new BA.1 omicron variant is probably somewhat better than tixagevimab/cilgavimab, but both may work less well against the BA.2 variant. Higher doses may be able to overcome this.”
Outpatient Treatment: Sotrovimab
For Dr. Shah and colleagues, outpatient treatment indications are based on the COVID-19 severity and timing of symptoms, degree of immunocompromise, age, other risk factors for severe disease, and vaccination status.
“We focus on patients with hematologic malignancy who are either within 1 year of hematopoietic cell transplantation or CAR T-cell therapy or have received B-cell–depleting therapies in the prior 6 months, and those with chronic lymphocytic leukemia, myeloma, hypogammaglobulinemia, or an acute leukemia who are undergoing active treatment,” said Dr. Shah. “In addition, patients who are older than age 65 and patients with hematologic cancer who are not fully vaccinated are prioritized.”
In terms of timing, both Drs. Shah and Boeckh emphasized that earlier treatment is associated with a better chance of response. Under the EUA, sotrovimab, a long-acting monoclonal antibody, can be given up to 10 days from symptom onset.
“For the treatment of mild-to-moderate illness due to the Omicron variant, sotrovimab is the preferred treatment option,” said Dr. Shah, who noted that interim analysis of the randomized COMET-ICE study showed sotrovimab reduced the risk of disease progression.1 “If infection with BA.2 [a subvariant of Omicron] is suspected, however, the monoclonal antibody bebtelovimab should be used instead.”
Outpatient Treatment: Nirmatrelvir/Ritonavir
Alternatively, the oral antiviral drug nirmatrelvir/ritonavir can be used if a patient does not have access to monoclonal antibody drugs or an infusion center. Interim analysis of phase II/III data showed that compared with placebo, nirmatrelvir/ritonavir reduced the risk of hospital admissions and deaths by 89% among people with COVID-19 who are at high risk of severe illness.2 According to Dr. Boeckh, however, it is important to ensure that no significant contraindications due to drug-drug interactions exist with nirmatrelvir/ritonavir.
“[Nirmatrelvir/ritonavir] has a bit of complexity, including several drug-drug interactions due to ritonavir, which is a CYP3A inhibitor,” he said. “This is important for transplant patients who are receiving immunosuppressive and other drugs. You must be careful with the list of prescribed medications.”
If no other options are available, the antiviral drug molnupiravir may also be considered for mild-to-moderate COVID-19 in the outpatient setting, but safety and efficacy data have not been too favorable.3
“Molnupiravir has mutagenic potential and can cause bone and cartilage toxicity. It is also the least effective antiviral,” said Dr. Shah. “For these reasons, molnupiravir should be used only when other options are not available.”
Nirmatrelvir/ritonavir and molnupiravir should be used within 5 days of symptom onset.
Inpatient Treatment: Remdesivir
For mildly symptomatic patients, intravenous remdesivir, a broad-spectrum antiviral agent, can be used within 7 days of symptom onset. For hospitalized patients requiring supplemental oxygen, said Dr. Shah, dexamethasone is added. Baricitinib can be added within 14 days of a positive COVID-19 polymerase chain reaction test in patients with ongoing or progressive symptoms on remdesivir and dexamethasone, if they are on high-flow oxygen or noninvasive ventilation.
“If patients have access to a health-care facility or are already hospitalized for non–COVID-related reasons, a 3-day course of remdesivir is a good option,” Dr. Shah continued. “For hospitalized patients with oxygen requirement, remdesivir and dexamethasone remain the backbone of treatment. In those with rapid disease progression despite these treatments, interleukin-6 inhibitors approved for COVID -19 should be considered.”
Remdesivir has been studied in many trials for inpatient use, including ACTT-1, DisCoVeRy, and GS-US-540-5773.4-6 The drug was also studied for outpatient use in PINETREE.7
“Remdesivir was one of the first antivirals studied,” said Dr. Boeckh. “Although it wasn’t that effective late in the disease course, it really seems to work when it is given early. That’s the recurring theme with COVID-19: if you intervene early, you will see a good effect.”
Dr. Boeckh added: “Due to the complexity of administration and logistical challenges associated with outpatient administration, we presently don’t use remdesivir upfront, but the data for it look as good as for the other drugs.”
Dexamethasone use is supported by the RECOVERY trial and additional meta-analyses.8 Tocilizumab was studied in the REMAP-CAP and RECOVERY trials.9 The COV-BARRIER trial provides data for baricitinib.10
The Future: Drugs, Diagnostics, Vaccines, and Variants
According to Dr. Shah, the past 2 years have seen significant changes in the response to COVID-19, but the availability of vaccines has made the largest difference in the severity of disease and need for hospitalization. Dr. Shah and fellow oncologists continue to work in collaboration with their infectious disease colleagues to adjust the treatment algorithm as more evidence-based options become available.
One must be vigilant about how these compounds perform against future possible variants…. But since we have a variety of therapeutic options, I am hopeful that some of them will continue to work.— Michael Boeckh, MD, PhD
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“With the rise of the Omicron variant, a few of the treatments that were very useful in 2021 are no longer effective,” said Dr. Shah. “As the virus changes and as more research becomes available, we have adjusted to the options during each wave to try to limit the impact on our patients, so they can continue treatment for their cancer and stay as safe as possible throughout the pandemic, regardless of their need for treatment or disease status.”
Dr. Boeckh underscored the availability of effective therapies, ongoing drug development, and the ubiquity of diagnostics as major accomplishments in the fight against COVID-19. These drugs seem to work against the common variants, however, he also expressed caution about the emergence of another variant.
“Nobody knows what’s going to happen next fall or even earlier,” said Dr. Boeckh. “Cases are decreasing, and we are better prepared than we were 2 years ago, but we are on high alert for the next season because of what happened to some of the other monoclonal antibodies that were rendered obsolete for the Omicron variant.”
Dr. Boeckh continued: “A large clinical trial was planned and then had to be canceled because it no longer made sense to continue as the monoclonal had lost its efficacy. One must be vigilant about how these compounds perform against future possible variants, both for drugs and for monoclonals, but since we have a variety of therapeutic options, I am hopeful that some of them will continue to work.”
In addition, Dr. Boeckh noted that COVID-19 may always pose a threat to patients who are immunocompromised. Even if there is herd immunity in the general population, he said, either through vaccination, natural infection, or several natural infections, an allogeneic transplant or other highly immunosuppressive therapies wipe out that immunity. Patients undergoing allogeneic transplantation must thus wait at least 3 months until vaccination. According to Dr. Boeckh, monoclonal antibodies can help bridge these patients over those first few months of intense immunosuppression.
Given these risks for the immunocompromised, Dr. Boeckh and colleagues are also trying to understand the impact of donor immunity. “The principle of bone marrow transfer or stem cell transplantation is replacing the recipients’ immune systems with the donors’,” he said. “We have an ongoing multicenter, observational study to figure out what the impact is for fully boosted donors and/or those with natural immunity and to learn what that means for the success of vaccination in the recipient.”
DISCLOSURE: Dr. Shah has received research support from Janssen, Amgen, and Beyond Spring. Dr. Boeckh has received research support from Vir Biotechnology, GlaxoSmithKline, Regeneron, and Merck; and has served as a consultant for Vir Biotechnology, Gilead, and Moderna.
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10. Marconi VC, Ramanan AV, de Bono S, et al: Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER) [published correction]. Lancet Respir Med 9:1407-1418, 2021.
