Experts discuss cancer care and research in the age of COVID‐19

Early during the pandemic, some experts were concerned that immunotherapies could worsen immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, by blocking certain immune checkpoints. Conversely, others suggested that these therapies might have the opposite effect; they noted that programmed cell death 1 (PD-1) checkpoint inhibitors could potentially reduce the risk of viral infections, including COVID-19, according to Antoni Ribas, MD, PhD, president of the American Association for Cancer Research (AACR) and a professor of medicine, surgery, and medical and molecular pharmacology at the University of California, Los Angeles. However, 6 months after the virus began to spread worldwide, scientists at the AACR's annual meeting, held virtually in July 2020, presented additional data on the topic. According to their research, “there doesn't seem to be a difference in the rates of COVID-19 infection between people who are and are not on immunotherapy,” Dr. Ribas says. “There also doesn't seem to be a difference in the rate of complications or outcomes.” Still, the investigation is in the early stages, and current evidence is indirect because investigators are unable to conduct a randomized controlled study in different groups of patients with COVID-19 who either are or are not receiving immunotherapy, Dr. Ribas says. He notes that mouse models appear to link immunotherapy to reduced rates of viral infection. One reason immunotherapy's impact on SARS-CoV-2 was uncertain at the pandemic's start was that early studies of COVID-19 in patients with cancer had not controlled for associated comorbidities such as inflammatory lung disease. This disease is linked to worse outcomes for patients with cancer who have the virus. Because current or former smokers are at greater risk for inflammatory lung disease, they are more predisposed to worse COVID-19 outcomes. Current or former smokers also have more mutations in their lung cancers that make them more likely to receive PD-1 inhibitors in comparison with nonsmokers, who are more likely to receive targeted therapies. These differences may account for scientists' initial assumption that immunotherapy caused worse outcomes in cancer patients with COVID-19, Dr. Ribas says. Moreover, many patients with cancer were advised at the start of the pandemic not to go to clinics for immunotherapy or other treatments to avoid possible exposure to SARSCoV-2. However, as clinics adapted to the pandemic climate by implementing prescreening measures, staggering appointment scheduling, and devising new methods to administer treatments, this was deemed unnecessary. “I know of no COVID-19 outbreaks in oncology clinics,” says Dr. Ribas, who primarily treats patients with melanoma. “And cancer immunotherapy is particularly justified when you look at the risk/benefit ratios.” Although Dr. Ribas and his colleagues initially told some patients to postpone certain treatments, they quickly pivoted to administering chemotherapy and immunotherapy in different regimens to reduce the frequency of clinic visits. Patients receiving the PD-1 inhibitors nivolumab and pembrolizumab, for example, were treated once a month instead of every 2 weeks, and once every 6 weeks instead of every 3 weeks, respectively. These antibodies are infused at higher doses that remain in the body for a longer time but do not increase toxicities, he adds, noting that patients have welcomed the change of fewer clinic visits. With the establishment of patient registries, researchers will continue to monitor long-term outcomes for cancer patients with COVID-19, including those treated with immunotherapy. Two leading registries are the ESMO-CoCARE Registry, an international collaborative database, and the COVID-19 and Cancer Consortium, an electronic database built and maintained by researchers at the Vanderbilt University Medical Center in Nashville, Tennessee. Jia Luo, MD, a medical oncology fellow at Memorial Sloan Kettering Cancer Center in New York City, was one of several investigators to present summaries of their findings on the use of immunotherapy treatments amid the COVID-19 pandemic at the AACR's meeting. She discussed her group's evaluation of 70 patients who were treated in March and April. The majority had a smoking history along with metastatic or active lung cancer. Approximately 59% received PD-1 blockade treatment, and 23% of the patients in the group died. “We found no significant increase in hospitalization, ICU admittance, intubation, or death due to COVID-19 with PD-1 blockade exposure,” she says. “Recovery occurred in 65% of patients.” She also notes that recent PD-1 blockade treatment with or without chemotherapy was not associated with severity of outcomes. Meanwhile, Layne Weatherford, PhD, a postdoctoral researcher at the University of Cincinnati, presented findings on a study of immunotherapy's impact on patients with cancer and COVID-19. Those patients had a higher mortality rate than people with COVID-19 who did not have cancer. Because immune checkpoint inhibitors can increase inflammatory cytokine secretion and predispose patients to cytokine storm, Dr. Weatherford and his colleagues hypothesized that these therapies might lead to complications in patients with COVID-19. Their preliminary analysis shows that immunotherapies may lead to cytokine storm and suggest that ongoing investigation will help oncologists to learn whether immunotherapy should be postponed in cancer patients with severe COVID-19 infections. Their research also suggests that the antidiabetic drug metformin, which decreases certain inflammatory cytokines, may be a potential treatment in these cases. Aljosja Rogiers, MD, PhD, a medical oncology fellow at Melanoma Institute Australia, presented preliminary findings from a study of 113 patients with COVID-19 who were being treated with immunotherapy at 19 hospitals in Europe, North America, and Australia. The investigators concluded that although the mortality rate of COVID-19 in patients receiving immune checkpoint inhibitors is higher than rates reported for the general population without comorbidities, it may not be higher than rates reported for the cancer population. The researchers added that cancer patients with COVID-19 who are receiving immunotherapy may not have symptoms and that a proportion of them may continue the treatment. Correlative analyses are ongoing. A separate AACR virtual session focused on how oncology leaders have responded to disruptions caused by the pandemic in cancer clinical trials. Panel members included representatives from academia, pharmaceutical companies, the National Cancer Institute (NCI), and the Food and Drug Administration. “This has been one of the most remarkable 4 months I've experienced in my 40-year career,” says James Doroshow, MD, the NCI's deputy director for clinical and translational research. “From the middle of March to the first or second week of April, we experienced a 40% drop in accruals and were faced with instantaneously making changes to our clinical trials program that enrolls about 25,000 patients per year.” Those changes included halting onsite auditing, shipping investigational agents directly to sites, and no longer requiring patients to come to clinics for routine services such as laboratory tests. There was also less emphasis placed on minor deviations with a greater focus placed on major outcomes. These adjustments, he says, were essential and helped to raise their trial accrual rates slightly. Dr. Doroshow and his colleagues already had been reassessing how to improve clinical trial accruals, simplify the process, and reduce costs. The pandemic simply necessitated that they make those changes much faster, he says. Patricia LoRusso, DO, associate director of experimental therapeutics at Yale Cancer Center in New Haven, Connecticut, notes that the early novel coronavirus surge in the state forced her and her colleagues to act quickly. They closed clinical trial recruitment and relocated patients to other states and hospitals to free up beds for those sickened by COVID-19. They initiated telehealth for many services and used specialized equipment to virtually check vital signs or relied on visiting nurses to do so in patients' homes. Patients also were permitted to go to nearby laboratories for tests. “There are ways of protecting patient safety and data integrity while allowing patients to take care of things closer to home,” she says. Panel members agreed that being forced to adapt so quickly helped them to adopt strategies to make clinical trials speedier, more convenient, and more efficient without compromising safety or quality. As a result, they anticipate a more streamlined process that will attract more participants in the future. “Allowing us to democratize clinical research and clinical trial participation for patients will help us recruit more underserved populations, which has always been challenging,” Dr. LoRusso says. “One of the main issues has been getting them to the centers.” Dr. Doroshow also pointed to the speed with which the NCI initiated the NCI COVID-19 in Cancer Patients Study at 650 sites. This natural history study will collect blood samples, medical information, and medical images from 2000 patients with cancer who also have COVID-19 and follow them for up to 2 years. “We stopped all new trial accrual at the end of April to get this up and running in the hope that it will help us understand longitudinally what the outcomes are,” he says. “We were very lucky to get additional funds to support these studies and get it off the ground in 5 weeks.” The NCI also is actively planning randomized trials comparing different processes of conducting clinical research. According to Dr. Doroshow, the goal is to determine whether the same high-quality research results will still be achieved with reductions in some data, visits, and expenditures.