Teaching an Old Dog New Tricks: Repurposing Cancer Drugs to Combat COVID-19

In response to the novel coronavirus disease 2019 (COVID-19) pandemic, investigators around the world channeled their efforts into acquiring a better understanding of the virus so that they could rapidly identify any weapons that may be used in the fight against its spread; this included turning to tried-and-true cancer drugs to see whether they could be repurposed to address this pressing need.

In an oral presentation delivered during the 2021 AACR Virtual Meeting on COVID-19 and Cancer, David C. Fajgenbaum, MD, MBA, MSc, the director of the Center for Cytokine Storm Treatment & Laboratory of the University of Pennsylvania, shared how his experience of having fallen critically ill with idiopathic multicentric Castleman disease, a rare and life-threatening disorder, led him down a career path that would explore new ways in which older drugs could be leveraged to save lives.¹

“When I became critically ill with idiopathic multicentric Castleman disease, I experienced multiorgan failure and became very, very sick,” Fajgenbaum shared. “I eventually began a race to try to find a drug that I could repurpose to save my life…Thankfully, I did fine one such drug by identifying the mTOR signaling pathway as a therapeutic target...This led me to my current career, which is leading a center that is focused on cytokine storm treatment…and dissecting these disorders to identify therapeutics that can be effective.”

In his talk, Fajgenbaum shared lessons from his work in Castleman disease and other cytokine disorders and the overlap with COVID-19, highlighted ongoing efforts to repurpose cancer drugs to combat the virus, and closed with future research directions.

Learning About Cytokine Storm

Patients with idiopathic multicentric Castleman disease and those with COVID-19 can similarly experience cytokine storm in which they both experience multiorgan failure and require the assistance of a ventilator.

“But is cytokine storm really the right term for COVID-19? This is something that needs to be debated and it has been highlighted a number of times over the past year,” said Fajgenbaum. “[We] tried to define what cytokine storm is versus what it is not, because we need a definition to decide whether something fits within it.”

Cytokine storm and cytokine release syndrome are life-threatening systemic inflammatory syndromes that are typically defined by elevated levels of circulating cytokines and immune cell hyperactivation that can be triggered by several therapies, pathogens, cancers, autoimmune conditions, and monogenic disorders.²

According to Fajgenbaum, cytokine storm can be defined as having the following:

• Increased cytokine levels
• Acute systemic inflammatory symptoms
• Secondary organ dysfunction
  • If in the presence of a pathogen, this must be worse than or beyond what would be expected from controlling the pathogen normally. If no pathogen is present, there must be cytokine-driven organ dysfunction.

“When we think about this definition of cytokine storm in relation to COVID-19, clearly the most severe cases meet the first 2 components of the definition. The third one, organ dysfunction beyond the normal response, is a challenging one to delineate,” said Fajgenbaum. “What I like to do to really dig into this last one is [consider] response to therapies. If you target a specific cytokine or immunosuppress a population of patients and their outcomes improve, then we can use that to infer that their organ dysfunction is due to excessive inflammation as opposed to just purely a normal response to pathogens.”

Fajgenbaum added that research has shown that dexamethasone, a drug that has been in circulation since the 1960s and has been utilized to decrease inflammation in several conditions and cancers, resulted in improved outcomes in patients with severe COVID-19 infection.3 Because of this, Fajgenbaum believes that patients with severe infection should fall within this definition of cytokine storm, whereas mild and moderate cases potentially would not.

Repurposing Old Weapons for New Battles

Several approaches are used to identify a drug that is being used in one condition to see whether it can be repurposed for use in another area, according to Fajgenbaum.

For example, high throughput drug screens can be used to test several compounds on a cell line. Artificial intelligence can be used to examine published databases to determine connections that may not be readily apparent. Translational research can also be conducted to identify potential targets. Once identified, databases can be used to determine which available drugs are able to bind to those targets. Then, the drug can be moved into mechanistic studies for further exploration.

“There are a few ways you can identify a drug that looks promising. Once identified, sometimes those drugs are already being given to patients with that condition and you can look at observational data to see whether any associations exist,” explained Fajgenbaum. “Other times, doctors will prescribe these drugs off label based on early anecdotal evidence. Then, you move forward to open-label clinical trials and randomized controlled trials, the goal being that you either get FDA approval and/or it is adopted in clinical practice.”

Launching the CORONA Project

In response to the pandemic, investigators around the world worked to see whether existing drugs could be repurposed for the virus. However, no overarching framework was established to collect all these data to have them available in one place. To address this, Fajgenbaum and colleagues launched the CORONA project.

The goal of the project is to serve as a central repository for all information on therapies that have been used against COVID-19.⁴ Additionally, investigators hope to examine the available data to determine which options may be most beneficial to which patients and to appropriately prioritize relevant clinical trials.

Fajgenbaum and colleagues conducted a systematic literature review to identify all treatments reported to be given to patients with COVID-19 and to evaluate the time to clinically meaningful response achieved. Over 90 volunteers reviewed 29,353 papers and extracted information on 273,177 patients. Over 400 treatments were identified in the review and all data are available in an open-source database. The team has partnered with Google Health, the FDA, and many other groups to better utilize the available data.

When looking at the first 9,152 patients included in the database, investigators found that corticosteroids were the third most frequently prescribed drug class, despite that international organizations like the World Health Organization recommended against using these agents in this capacity.^5,6 Corticosteroids were used by 26.1% (n = 392) of patients included in the review.

“We were also very surprised to see how much interferon administration there was outside of the United States,” noted Fajgenbaum. “No one was using interferon alpha or beta in the United States, but outside the country, it was actually the second most frequently reported agent.” Approximately 19% of patients (n = 1767) received interferon alpha or beta.

Lastly, investigators realized that it would be impossible to truly examine the efficacy of the agents or compare efficacy between the drugs, outside of performing a randomized controlled trial, because of the heterogenous natural history of COVID-19.

“If this disease was uniformly fatal, then certainly, if you see improvements you would get a sense of how these drugs work,” said Fajgenbaum. “But because most patients improve, if someone improves while they’re taking a drug, you don’t know whether they would have improved regardless.”

Promising Inpatient/Outpatient Agents

In the inpatient setting, Fajgenbaum shared several agents that have been examined in randomized controlled trials.

For example, dexamethasone has been evaluated in the RECOVERY trial and was shown to reduce mortality by approximately one-third in patients with COVID-19 who were on ventilators (rate ratio [RR], 0.65; 95% CI, 0.48-0.88; P = .0003). Among patients who received oxygen only, dexamethasone was found to reduce deaths by one-fifth (RR, 0.80; 95% CI, 0.67-0.96; P = .0021).³

Moreover, tocilizumab (Actemra) was found to reduce the likelihood of progression to the composite outcome of mechanical ventilation or death in hospitalized patients with COVID-19 pneumonia who were not receiving mechanical ventilation.⁷ However, it was not found to improve survival. “There may be a signal if you start tocilizumab within 24 hours of admission to the intensive care unit, but not at any other period; it’s a very narrow window,” noted Fajgenbaum.

The use of thromboprophylaxis with enoxaparin in patients hospitalized with SARS-CoV-2 infection was found to be associated with lower in-hospital mortality (odds ratio, 0.53; 95% CI, 0.40-0.70) versus no enoxaparin treatment, according to data from a cohort study.⁸ “Enoxaparin seems to be effective late, in severe cases but no randomized controlled trials have read out yet,” said Fajgenbaum.

The combination of baricitinib and remdesivir (Veklury) was found to reduce time to recovery for patients hospitalized with COVID-19.⁹ The most benefit with this approach was observed in patients who required high-flow oxygen or non-invasive ventilation during their hospital stay; their median time to recovery was reduced by 8 days, going from 18 days to 10 days.

Data from the COVID-19 and Cancer Consortium also showed that remdesivir alone was linked with a lower mortality rate in patients with cancer who were infected with the virus versus other drugs examined in the population.¹⁰

Most recently, topline data from the COLCORONA trial showed that the anti-inflammatory oral agent colchicine reduced the risk of death or hospitalization in patients with COVID-19 by 21% compared with placebo.¹¹ In patients with COVID-19, colchicine reduced the need for hospitalization by 25%, reduced the need for mechanical ventilation by 50%, and reduced deaths by 44%. “This way be one of the only drugs that has a benefit in a variety of settings,” noted Fajgenbaum.

For the outpatient setting, Fajgenbaum noted the potential of monoclonal antibodies, colchicine, arbidol, fluvoxamine, and nitazoxanide.

Future Directions

“We are going to continue to track drugs that are being repurposed and continue to identify promising drugs for clinical trials along with the FDA,” concluded Fajgenbaum. “A number of these drugs are already being used in the cancer setting…We’re going to continue to investigate the inflammatory response in COVID-19 and search for actionable candidate drug targets to figure out what should be targeted. Finally, we’re going to continue to advocate for drug repurposing beyond COVID-19.”

References

1. Fajgenbaum DC. Storming the castle: repurposing treatments for COVID-19. Presented at: 2021 AACR Virtual Meeting on COVID-19 and Cancer; February 3-5, 2021; Virtual.
2. Fajgenbaum DC, June CH. Cytokine storm. N Engl J Med. 2020;383(23):2255-2273. doi:10.1056/NEJMra2026131
3. Horby P, Lim WS, Emberson J, et al. Effect of dexamethasone in hospitalized patients with COVID-19: preliminary report. MedRxIv. Published online June 22, 2020. doi:10.1101/2020.06.22.20137273
4. CORONA Registry. Updated January 31, 2021. Accessed February 4, 2021. http://tabsoft.co/3rohAPn.
5. Fajgenbaum DC, Khor JS, Gorzewski A, et al. Treatments administered to the first 9152 reported cases of COVID-19: a systematic review. Infect Dis Ther. 2020;9(3):435-449. doi:10.1107/s401201-020-00303-8
6. WHO updates clinical care guidance with corticosteroid recommendations. News release. World Health Organization. September 2, 2020. Accessed February 4, 2021. http://bit.ly/36IJayJ
7. Salama C, Han J, Yau L, et al. Tocilizumab in patients hospitalized with Covid-19 pneumonia. N Engl J Med. 2021;384(1):20-30. doi:10.1056/NEJMoa2030340
8. Albani F, Sepe L, Fusina F, et al. Thromboprophylaxis with enoxaparin is associated with a lower death rate in patients hospitalized with SARS-CoV-2 infection. a cohort study. EClinicalMedicine. 2020;27:100562. doi:10.1016/j.eclinm.2020.100562
9. Baricitinib plus remdesivir shows promise for treating COVID-19. News release. National Institutes of Health. December 11, 2020. Accessed February 4, 2021. http://bit.ly/2YJmWIv.
10. Rivera DR, Peters S, Panagiotou OA, et al. Utilization of COVID-19 treatments and clinical outcomes among patients with cancer: A COVID-19 and Cancer Consortium (CCC19) cohort study. Cancer Discov. Published online July 22, 2020. doi:10.1158/2159-8290.CD-20-0941
11. Colchicine reduces the risk of COVID-19-related complications. News release. Montreal Heart Institute. January 22, 2021. Accessed February 4, 2021. http://bit.ly/2MzoAtX.