A vaccine for COVID-19 is currently the Holy Grail, but even if an effective vaccine were developed on a fast-track timetable, it may be effective in only a percentage of people, judging by existing flu vaccines, which show efficacy rates of approximately 45% and vary year by year. Until we have a vaccine, and even after that, effective drugs are needed to treat the manifestations of COVID-19. At the recent American Association for Cancer Research (AACR) Virtual Meeting: COVID-19 and Cancer, attendees heard about several approaches using available drugs that are being repurposed to treat the disease. Some of these treatments have promise—anti-inflammatory molecules, a histamine receptor 2 blocker, and an androgen receptor inhibitor—and are moving to later-phase studies.
“We are trying to extend knowledge of molecular characteristics of this disease and available drugs’ mechanism of action to develop therapies that mitigate deleterious effects of the virus.”— Keith Flaherty, MD
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“We are trying to extend knowledge of molecular characteristics of this disease and available drugs’ mechanism of action to develop therapies that mitigate the deleterious effects of the virus. In the midst of that, we have seen a theme of cancer therapeutics being repurposed in this first-wave response…. We are trying to reposition the pipeline of drugs developed to treat anti-inflammatory aspects of the disease. There is an enormous amount of activity in this field,” said session moderator Keith Flaherty, MD, of Massachusetts General Hospital, Boston.
Blocking IL-8 to Treat Hospitalized Patients With COVID-19
Charles G. Drake, MD, PhD, Co-Director of Cancer Immunotherapy Programs, Columbia University’s Herbert Irving Comprehensive Cancer, New York, described the rationale and design for a multicenter study in hospitalized patients with COVID-19 to evaluate an anti–interleukin (IL)-8 antibody.1 The study was designed by Principal Investigator Matthew Dallos, MD, Assistant Professor, at the Herbert Irving Comprehensive Cancer Center, and is being conducted at Columbia, but due to the decreasing number of patients with COVID-19 at that center, enrollment is now open to other centers.
“The pathology that results in death from COVID-19 is similar to that of adult respiratory distress syndrome [ARDS], and it remains poorly understood. Several models have been proposed to explain it,” Dr. Drake said.
Dr. Drake, Dr. Dallos, and colleagues are focusing on neutrophils and IL-8, which is secreted from infected epithelial cells. Neutrophils form structures called neutrophil extracellular traps, which are implicated in inflammatory pathology in ARDS, including tissue damage, delayed tissue repair, macrophage activation, and secretion of IL-1–beta, setting up inflammation in a positive feedback loop.
“[Neutrophil extracellular traps] have procoagulation effects on forming clots. A large portion of patients with COVID-19 who do poorly have clots. It could be that [neutrophil extracellular traps play a role in these processes,” Dr. Drake suggested.
Early studies suggest that targeting IL-8 may be of benefit in patients with COVID-19 with critical disease who express higher levels of IL-8. “IL-8 correlates with poor outcomes in ARDS, and patients with high IL-8 expression were more likely to die with COVID-19 in one study,” he explained. “Other studies show [high] IL-8 levels are associated with a poor outcome, as is [a high] neutrophil-to-lymphocyte ratio.”
BMS-986253 is a fully human monoclonal antibody that was developed to treat palmar-plantar pustulosis in patients with cancer who have a poor response to immune checkpoint blockade. BMS-986253 has been found to be safe in patients with cancer when used as monotherapy and in combination with anti–PD-1, he continued.
The ongoing randomized, controlled trial is enrolling patients with confirmed COVID-19 of less than 14 days’ duration who require inpatient hospitalization because of severe or critical respiratory disease. Patients are randomly assigned 2:1 to anti–IL-8 therapy with BMS-986253 at 2,400 mg every 2 weeks for two doses (n = 92) vs standard of care (n = 46). If patients remain in the hospital after two doses, anti–IL-8 therapy is given once more at the same dose. Planned enrollment is 120 patients. No other investigational therapy for COVID-19 is allowed except remdesivir, hydroxychloroquine, or a compassionate use agent.
The primary endpoint is change in a 7-point ordinal scale based on critical care measurement. Secondary endpoints include 28-day mortality, improvement in oxygenation, intensive care unit admission, safety, and hospitalization duration. Correlative studies of sera and inflammatory markers are being done.
“The study was open for patients with cancer after the first dozen patients with COVID-19 were treated, and we saw that the drug was safe and well tolerated. Patients with cancer can continue their anticancer therapy while on the trial,” Dr. Drake said.
Although he could not report on the data on the first group of patients treated thus far, Dr. Drake gave a snapshot of experience to date. The first two patients responded within 2 days and left the hospital, but then another patient was treated with the antibody and did not get better.
“Early results [in other patients] are promising. The therapy is nontoxic, and the trial is ongoing,” he stated.
Famotidine in Nonhospitalized Patients
“Severe COVID-19 has a high mortality rate, and therefore prevention of severe disease is important. However, there is currently no effective treatment for early-stage, mild to moderately severe disease in the outpatient setting. Anecdotally, famotidine was associated with improved clinical outcome and in a retrospective cohort study in hospitalized patients with COVID-19. As a first step, we decided to conduct a case series,” said Tobias Janowitz, MD, PhD, of Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
“Anecdotally, we saw that famotidine was associated with improved clinical outcome in hospitalized patients with COVID-19. We decided to do our own study.”— Tobias Janowitz, MD, PhD
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At the start of the retrospective analysis, the researchers hypothesized that famotidine, a histamine H2-receptor antagonist, would improve outcomes in nonhospitalized patients with COVID-19.2 The case series included 10 consecutive patients who self-administered high-dose famotidine (oral doses of up to 80 mg three times daily). There were no exclusions for age, gender, ethnicity, or body mass index.
Patient questionnaires were used to evaluate symptoms longitudinally, such as general unwellness, cough, shortness of breath, fatigue, headache, and anosmia. Scores ranged from 1 (no symptoms) to 4 (severely affected, ie, need help from others, need to rest most of the day).
Self-reported data from all 10 patients suggested that recovery (both symptomatic and physiologic) was correlated with famotidine use. In several patients, oxygen saturation improved after starting famotidine, which led to increased physical activity and walking distance.
“All patients improved within 1 day and continued to improve for 2 weeks after starting famotidine,” Dr. Janowitz said. “Famotidine was well tolerated on an outpatient basis at oral doses up to 80 mg/d.”
Duration of pretreatment symptoms did not seem to affect the response to famotidine. One patient who had symptoms 4 days prior to starting famotidine and another with symptoms for 26 days prior improved within 2 to 7 days of starting the drug.
“This case series, of course, has limitations and should be considered a step as part of ongoing work. After this preliminary study, we are planning to do a prospective randomized double-blind clinical trial in outpatients with mild-to-moderate symptoms of COVID-19,” Dr. Janowitz told the audience.
“We are extremely interested in mechanism of action. We and others have not identified an inhibitory effect on viral proteases, and we investigate whether famotidine inhibition of the histamine receptor signaling on host cells may be the mechanism of action,” he said.”
“Even without further mechanistic insight, famotidine is safe, inexpensive, and could be used on a widespread scale,” said session moderator Dr. Flaherty.
Tocilizumab: IL-6 Inhibitor
There has been a great deal of interest in tocilizumab for the treatment of severe COVID-19, given its established use to treat cytokine-release syndrome in patients on chimeric antigen receptor (CAR) T-cell therapy. A preliminary study presented by Alexandra Cabanov, a graduate student researcher at the University of Chicago, found that tocilizumab did not inhibit the induction of anti-COVID antibodies.3
“We and others were concerned that interrupting IL-6 signaling [with tocilizumab] could blunt the antibody response to COVID 19 infection.”— Alexandra Cabanov
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“IL-6 is a cytokine implicated in the cytokine storm observed in patients with COVID-19. Tocilizumab is a humanized IL-6 antibody that has been repurposed to treat patients with severe COVID-19 infection. IL-6 is crucial in the development, maturation, and survival of plasma cells, and it is critical in clearing viral infection. We and others were concerned that interrupting IL-6 signaling [with tocilizumab] could blunt the antibody response to COVID 19 infection,” Ms. Cabanov said.
The investigation she reported enrolled 20 patients treated with tocilizumab who were participating in the COVIDOSE study (of low-dose tocilizumab) and 11 patients treated off study with tocilizumab. These patients were compared with a control group of 37 patients (27 of whom received remdesivir). The results showed that blocking IL-6 with tocilizumab did not impede the generation of antibodies to COVID-19 compared with controls.
Both groups were treated with tocilizumab and comparable peak titers with similar kinetics in patients vs controls. Controls and tocilizumab-treated patients generated a comparable antibody response to COVID-19 infection.
During another session, Garth Strohbehn, MD, MPhil, a third-year fellow at the University of Chicago, discussed the COVIDOSE trial.4 “A study in China, where patients with COVID-19 improved within 24 hours of tocilizumab (6 mg/kg), led to off-label use of the drug. Tocilizumab was associated with a lower risk of [the need for] ventilation in patients who were not ventilated. We wanted to know how generalizable this approach is, given that there are shortages of tocilizumab,” he said.
Garth Strohbehn, MD, MPhil
“For those of us involved in the field of interventional pharmacoeconomics, this raised the question of whether tocilizumab shortages were driven by excessive dosing. We decided to study whether we could use lower doses [than are used to treat rheumatoid arthritis] in patients with COVID-19,” he told the audience.
The authors designed a single-arm, adaptively designed, phase II trial of low-dose tocilizumab in patients with COVID-19 with pneumonia. Patients, all of whom had elevated C-reactive protein, were divided into two groups: those with risk factors for COVID-related mortality (n = 12), who were treated with tocilizu-mab at 200 mg and, later, 120 mg; and the second group (n = 20), who received tocilizumab at 80 mg and, later, 40 mg. All patients had the option for repeat dosing. Controls were derived from a data warehouse.
No patient has been lost to follow-up. Compared with retrospective controls, patients treated with tocilizumab had more rapid control of temperature. The likelihood of resolution of fever was not related to the dose of tocilizumab.
A more rapid decline in C-reactive protein levels was observed with tocilizumab compared with retrospective controls. Again, this was not related to the dose.
“Low-dose tocilizumab appears to be biologically active in COVID-19 pneumonia. A randomized controlled trial is needed. We do not advocate the use of tocilizumab outside of a clinical trial. Using a low dose may extend effective supplies of tocilizumab 3- to 10-fold,” Dr. Strohbehn noted.
Dr. Flaherty commented: “It feels like we are behind where we would like to be, given the widespread use of tocilizumab for COVID-19. It is reassuring to see these data. I’ve lost track of the number of tocilizumab studies in COVID-19. I would hope in the next month or two, we will see high-level announcements about whether this is a therapy that should be adopted,” he said.
Repurposing Endocrine Therapy
“There is an intriguing scientific hypothesis behind repurposing endocrine therapy for the treatment of COVID-19,” explained Catherine H. Marshall, MD, MPH, of Johns Hopkins University School of Medicine, Baltimore.
Catherine H. Marshall, MD, MPH
“There are important sex differences in COVID-19. Death from COVID-19 disproportionately affects men. More men are hospitalized with the disease and account for about 80% of deaths from severe cases of the virus,” she said. “Although the death rate increases with age, males have higher rates of death at all ages.”
TMPRSS2 is an enzyme that is highly expressed in the prostate, upregulated by testosterone, and downregulated by antiandrogens. COVID-19 requires both TMPRSS2 and ACE2 to enter the cells. TMPRSS2 is a serine protease that primes the spike protein in COVID-19, a critical step in viral entry to cells. ACE2 is the receptor used for entry into the host cell and may also be altered by hormone levels.
Previous research has suggested that estradiol may have beneficial effects on acute lung injury. Dr. Marshall and coauthors hypothesized that hormones may be partially responsible for the gender disparity in COVID-19, with high levels of testosterone being harmful and high levels of estradiol being helpful.
“Additional epidemiologic evidence suggests that hormones modulate the disease course in COVID-19,” she continued. “A large epidemiologic study of men with prostate cancer showed a greater risk of developing COVID-19 infection if they were not on androgen-deprivation therapy compared to those who were.”
Dr. Marshall and colleagues designed the phase II RECOVER trial to test the hypothesis that androgen-deprivation therapy (bicalutamide) can improve outcomes in COVID-19.5 The study plans to enroll 60 patients (men and women aged 18 years or older) hospitalized for COVID-19 with minimal respiratory symptoms and randomly assign them 1:1 to bicalutamide for 7 days vs standard of care. The primary outcome will be the percentage of patients with clinical improvement at day 7 compared to controls, based on the World Health Organization categorial scale of clinical improvement. Secondary endpoints are all-cause mortality at 28 days, worsening disease, change in hormone levels, and viral endpoints. Enrollment started in August 2020.
“The reason we chose bicalutamide is because it is an antiandrogen that downregulates TMPRSS2 in androgen-dependent cell lines and increases estradiol levels. In addition, we think upregulation of estrogen improves immune response, and studies in mouse models suggest that it may attenuate lung injury,” she continued. “Also, bicalutamide is inexpensive, widely available as a generic drug, and causes only mild side effects.”
“We think that bicalutamide would have the greatest impact when viral replication is still significant and there may be some mild pulmonary symptoms, but before advanced disease develops,” she said.
BTK Inhibition in Severe COVID-19
“COVID-19 has stages. Early infection is characterized by fever and leukopenia, which can resolve spontaneously. After about 7 days, some patients go on to a pulmonary phase characterized by shortness of breath and hypoxia, with increased inflammatory markers and a hypercoagulable state. Some patients recover, but after day 10, some go on to hyperinflammation characterized by sky-high markers. This is a dangerous state and can lead to death,” explained Louis M. Staudt, MD, PhD, of the National Cancer Institute. “We wanted to find a therapeutic intervention to prevent the need for ventilation and death.”
Louis M. Staudt, MD, PhD
Wyndham Wilson, MD, PhD
Dr. Staudt and senior author Wyndham Wilson, MD, PhD, selected the Bruton’s tyrosine kinase (BTK) inhibitor acalabrutinib for study. “We knew that BTK inhibitors could block the innate immune response. We have been using this class of drug to treat lymphomas,” said Dr. Staudt.
The study was conducted at five sites and enrolled 19 patients hospitalized with moderate to severe COVID-19.6 Eleven patients were on supplemental oxygen with high-flow nasal cannulation, and eight were intubated on mechanical ventilation. Acalabrutinib was given off-label at the usual dose for 10 to 14 days. Lab studies and inflammatory markers were measured. “These patients were quite sick and had comorbidities,” he said.
In patients on supplemental oxygen, improvement in oxygenation, inflammation, and absolute lymphocyte count was observed within 1 to 3 days. Of the 11 patients, 9 were discharged; 1 was in rehabilitation with supplemental oxygen, and 1 patient died.
“We felt the improvement was likely due to acalabrutinib,” Dr. Staudt said. “Ventilated patients had a more difficult time, but trends were in the same direction. Two of the eight patients were extubated and discharged home,” he continued. In the ventilated group of eight patients, four died. “This was a more heterogeneous group,” he noted.
“We think the therapeutic efficacy [of acalabrutinib] is strongly correlated with reduced inflammatory markers. Acalabrutinib targets the source of hyperinflammation in COVID-19,” he stated.
Based on these results, a randomized controlled trial comparing acalabrutinib vs best supportive care is underway in hospitalized patients with moderate-to-severe COVID-19. “The plan is to piggyback 50 patients in the phase II randomized trial with 500 patients from around the world in phase III, if phase II pans out,” he said. Endpoints will be outcomes at 28 days.
“Results so far [in all studies] suggest that different treatments are required for different stages of COVID-19. For early COVID-19, remdesivir and famotidine appear to be helpful. For patients with cytokine storm, dexamethasone appears to be effective. Perhaps the BTK inhibitor is useful ‘at the trunk of the tree’ representing severe COVID-19,” he said, showing a diagram of a tree representing various treatment options for severe COVID-19 in the branches.
“With these trials of novel approaches, we are witnessing the first order of investigation on top of existing standard of care. We are all mindful about rational combinations and thinking about where the field should go next. Is it possible to aggregate enough knowledge to design rational combinations to study in COVID-19? We need to consider the consequences. We may be able to benefit or prevent thrombotic complications, if we can identify the root of the problem or the trunk of the tree,” Dr. Flaherty said.
“We all wish there were more mature antiviral strategies that were impactful and could be deployed earlier. We are still stuck with the current situation, and we need to develop regimens to get in front of each of the manifestations of the disease. Today we heard provocative data from uncontrolled analyses, and most of these studies are open. These talks were spectacular,” he commented.
DISCLOSURE: Dr. Flaherty has served as a consultant for Boston Biomedical, Lilly, Novartis, and Takeda; and owns equity in/is a board member for ALX Oncology, Apricity, Checkmate Pharmaceuticals, Clovis Oncology, Kinnate, Monopteros, PIC Therapeutics, Oncoceutics, Strata Oncology, Tvardi, Vibliome, and xCures. Dr. Drake holds stock or other ownership interests in Compugen, Harpoon Therapeutics, Kleo Pharmaceuticals, Tizona Therapeutics, Urogen Pharma, and Werewolf; has served in a consultingor advisory role for AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, Compugen, F-Star, Ferring, Genocea Biosciences, Janssen Oncology, Kleo Pharmaceuticals, Merck, Merck Serono, Pfizer, Pierre Fabre, Roche/Genentech, Shattuck Labs, Tizona Therapeutics, Urogen Pharma, and Werewolf; has received institutional research funding from Bristol Myers Squibb; holds institutional intellectual property licensed to Bristol Myers Squibb and Potenza Therapeutics; and has been reimbursed for travel, accommodations, or other expenses by the AACR, ASCO, Merck Sharp & Dohme, Pfizer, and Roche/Genentech. Dr. Marshall has served in a consulting or advisory role for Bayer Pharma, Dendreon, and McGraw-Hill and has been reimbursed for travel, accommodations, or other expenses by Dava Oncology. Dr. Janowitz, Ms. Cabanov, Dr. Strohbehn, Dr. Staudt, and Dr. Wilson reported no conflicts of interest.
1. Drake C: Blocking interleukin-8 to treat hospitalized patients with COVID-19. AACR Virtual Meeting: COVID-19 and Cancer. Presented June 20, 2020.
2. Janowitz T, Gablenz ET, Pattinson DJ, et al: Famotidine use and quantitative symptom tracking for COVID-19 in non-hospitalized patients. AACR Virtual Meeting: COVID-19 and Cancer. Abstract S04-01. Presented June 20, 2020.
3. Cabanov A, Flood BA, Bloodworth J, et al: Treatment with tocilizumab does not inhibit induction of anti-COVID-19 antibodies in patients with severe SARS-C0V-2 infection. AACR Virtual Meeting: COVID-19 and Cancer. Abstract S04-02. Presented June 20, 2020.
4. Strohbehn G: COVIDOSE: Low-dose tocilizumab in the treatment of COVID-19 pneumonia. AACR Virtual Meeting: COVID-19 and Cancer. Presented June 22, 2020.
5. Marshall CH, Yegnasubramanian S, Wang H, et al: A phase II trial to promote recovery from COVID-19 with endocrine therapy. AACR Virtual Meeting: COVID-19 and Cancer. Abstract IA09. Presented June 20, 2020.
6. Roschewski M, Sharman JA, Roswarski J, et al: Inhibition of Bruton tyrosine kinase in patients with severe COVID-19. AACR Virtual Meeting: COVID-19 and Cancer. Presented June 20, 2020.