COVID-19 and cancer: Outcome predictors and potential use of immunotherapy
Cancer patients infected with coronavirus disease 2019 (COVID-19) appear to be at higher risk of severe outcomes, including death, but cancer type and treatment serve as better predictors, according to recent research presented at the American Association for Cancer Research (AACR) 2020 Virtual Annual Meeting I.
At the time of writing, COVID-19 has spread to more than 200 countries and territories, affecting an estimated 4.5 million people and killing over 300,000. Cancer, on the other hand, is newly diagnosed in 18 million people and takes the lives of 10 million every year.
“We have invited physician scientists who are at the epicentre of the COVID-19 pandemic, taking care of patients with cancer. They gathered prospective information to understand the effects of COVID-19 on patients with cancer, are testing new treatments, and are making this knowledge available to the global research community, so we can all benefit from their experience,” said Professor Antoni Ribas from UCLA Medical Center, Los Angeles, California, US, chairperson of the COVID-19 and cancer plenary session of the meeting.
Haematological, lung cancer, recent chemo associated with higher risk of severe COVID-19 outcomes
Cancer patients are more susceptible to infections due to chronic comorbidities, overall poor health, and immunosuppression caused by cancer itself and anticancer treatments. [CA Cancer J Clin 2016;66:115-132] As a consequence, some cancer patients who contract the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may experience more severe outcomes than the general population.
A multicentre study involving 14 hospitals in Hubei Province, China, the epicentre of the 2019–2020 COVID-19 outbreak, collected and analyzed clinical characteristics and outcomes data such as cancer type, stage, treatment, intensive care unit (ICU) admission, development of severe/critical symptoms, utilization of invasive mechanical ventilation, and mortality from 105 hospitalized cancer patients and from 536 age-, hospital- and hospitalization time-matched non-cancer patients infected with SARS-CoV-2. [Cancer Discov 2020, doi: 10.1158/2159-8290.CD-20-0422]
“Compared with COVID-19 patients without cancer, patients with cancer had higher death rates [odds ratio (OR), 2.34; 95 percent confidence interval (CI), 1.15 to 4.77; p=0.03], higher rates of ICU admission [OR, 2.84; 95 percent CI, 1.59 to 5.08; p<0.01], higher rates of at least one severe or critical symptom [OR, 2.79; 95 percent CI, 1.74 to 4.41; p<0.01], and higher chances of needing invasive mechanical ventilation,” reported study author, Dr Hongbing Cai of the Department of Gynaecological Oncology, Zhongnan Hospital, Wuhan University, Wuhan, China.
In general, patients with cancer deteriorated more rapidly than those without cancer. This observation remained consistent after adjusting for age, sex, smoking, and comorbidities such as diabetes, hypertension and chronic obstructive pulmonary disease (COPD). “The consistency of observed ORs between the multivariate regression model and the unadjusted calculation confirms the association between cancer and severe events even in presence of other factors,” noted the authors.
Further analysis focused on the association of outcomes with cancer type. Patients with haematologic cancers (n=9), including leukaemia, lymphoma and myeloma, had a relatively high death rate (33.3 percent), high ICU admission rate (44.4 percent), high frequency of severe/critical symptoms (66.7 percent), and a high frequency of invasive mechanical ventilation (22.2 percent). “Patients with leukaemia, myeloma and lymphoma have a more compromised immune system than patients with solid tumours,” remarked the researchers. [Lancet 2014;383:1503-1516]
A French single-centre study of 137 cancer patients infected with SARS-CoV-2 also found that haematological malignancy (n=24) was associated with clinical worsening, defined as the need for oxygen supplementation of ≥6 L/min or death due to any cause (hazard ratio [HR], 4.6; 95 percent CI, 2.2 to 10.0; p<0.0001). [Barlesi F, et al, AACR 2020 Virtual Meeting I]
Wuhan patients with lung cancer (n=22) had the second highest risk of unfavourable outcomes, with a death rate of 18.2 percent, ICU admission rate of 27.3 percent, severe/critical symptoms occurring in half of the patients, and 18.2 percent requiring invasive mechanical ventilation. “Decreased lung function and severe infection in patients with lung cancer could contribute to worse outcomes in this subpopulation,” explained the researchers. [Lancet 2003;361:1773-1778; Lancet 2020;395:473-475]
Notably, patients with other cancer types who had lung metastases also showed higher risks of death, higher ICU admission rates, higher incidence of critical symptoms, and more commonly relied on invasive mechanical ventilation than patients without cancer (all p<0.01). However, patients with other cancer types without lung metastases showed no statistically significant differences in COVID-19 clinical outcomes compared with patients without cancer.
Patients who received immunotherapy (n=6) and those who underwent surgery (n=8) within 40 days prior to onset of COVID-19 symptoms tended to have high rates of death (33.3 percent and 25 percent, respectively) and frequently developed critical symptoms (66.7 percent and 62.5 percent, respectively). “However, patients with cancer who received radiotherapy [n=13] did not show statistically significant differences in severe outcomes vs patients without cancer,” highlighted the researchers.
According to the French single-centre study, treatment with cytotoxic chemotherapy during the last 3 months (n=48) was significantly associated with clinical worsening (HR, 2.60; 95 percent CI, 1.32 to 5.13; p=0.006). “Conversely, targeted therapy [n=18] or immunotherapy [n=12] received in the past 3 months had absolutely no impact on the risk of clinical worsening due to COVID-19 infection,” reported lead study author Dr Fabrice Barlesi of Gustave Roussy Cancer Campus, Villejuif, France.
A retrospective study of 28 cancer patients with SARS-CoV-2 infection from three hospitals in Wuhan, presented by Dr Li Zhang of the Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China, found that patients who received any anticancer treatment (chemotherapy, n=3; radiotherapy, n=1; targeted therapy, n=2; or immunotherapy, n=1) within 14 days prior to COVID-19 diagnosis had a higher risk of developing severe events (multivariate HR, 4.08; 95 percent CI, 1.09 to 15.32; p=0.037). [Zhang L, et al, AACR 2020 Virtual Meeting I; Ann Oncol 2020, doi: 10.1016/j.annonc.2020.03.296]
Use of oncology drugs in COVID-19 patients
Contrary to the findings of Cai and colleagues, Dr Paolo Ascierto of the National Tumour Institute in Naples, Italy, presented unpublished data from 400 cancer patients receiving immunotherapy, suggestive of beneficial effects of immune checkpoint inhibitors (ICIs) on the clinical course of COVID-19. [Ascierto PA, AACR 2020 Virtual Meeting I]
“One of the main concerns with using immunotherapy in cancer patients with COVID-19 is the possibility of an increased risk of pneumonia,” said Ascierto. “In the absence of data, this risk is only hypothetical, but it cannot be ruled out.”
“On the other hand, preclinical data suggest that ICIs could increase viral clearance and even be protective against viral infections,” he noted. [J Virol 2014;88:1636-1651] “Of the 400 patients receiving ICIs at our institute, only two tested positive for COVID-19. Both were receiving adjuvant anti–PD-1 therapy, both were asymptomatic, and tested negative for SARS-CoV-2 in less than 10 days.”
The ongoing phase II IMMUNONCOVID trial is evaluating the efficacy of the anti–PD-1 therapy nivolumab, the chloroquine analogue GNS561, or the anti–IL-6 receptor agent tocilizumab against standard of care in patients with advanced or metastatic cancer and SARS-CoV-2 infection.
In Zhang’s study, which collected follow-up data on 124 cancer patients treated with ICIs and their families, only one patient contracted SARS-CoV-2 at the hospital. Remarkably, a spouse of one of the patients receiving ICI treatment tested positive for COVID-19, but the patient remained COVID-19–negative.
“The rate of COVID-19 infection among patients receiving ICIs at our hospital [0.81 percent] is consistent with that in a general population of cancer patients [n=1,524; 0.79 percent] from another single cancer centre in Wuhan,” commented Zhang. [JAMA Oncol 2020, doi: 10.1001/jamaoncol.2020.0980]
Ascierto noted that some of the common adverse events (AEs) of cancer treatment (eg, immunotherapy-associated pneumonitis, fever associated with BRAF and MEK inhibitors) overlapped with COVID-19 symptoms and advised that before initiating the usual management of these potential side effects, patients’ COVID-19 status should be established. At the same time, due to the similarities between the two, some of the agents employed in the management of cancer treatment AEs may be efficacious in alleviating COVID-19 symptoms.
Autopsy results suggest that increased alveolar exudate caused by aberrant host immune response and inflammatory cytokine storm impedes gas exchange and contributes to the high mortality among severe COVID-19 patients. Pathogenic T cells and inflammatory monocytes incite an inflammatory storm with high levels of IL-6, making IL-6–targeting antibodies a promising treatment. [J Transl Med 2020;18:165] Indeed, tocilizumab was recently shown to improve immune-mediated AEs of PD-1 blockade in 79.4 percent of cancer patients (n=34). [J Oncol Pharm Pract 2019;25:551-557]
Ascierto shared two patient cases of COVID-19–related respiratory distress successfully treated with tocilizumab, leading to a recovery within 10 days. Based on these results, Ascierto and colleagues initiated the phase II TOCIVID-19 study, which enrolled 330 patients across Italy in just 24 hours, to evaluate the effect of tocilizumab on 1-month mortality rate.
Ascierto also presented a case series of 15 patients with acute respiratory distress syndrome treated with a single dose of another IL-6–targeting antibody, sarilumab, noting that 10 patients responded while five intubated nonresponders died. Ascierto highlighted two cases of patients who recovered within 24–72 hours of receiving sarilumab, adding that a phase II/III trial of sarilumab in hospitalized COVID-19 patients is ongoing in the US (NCT04315298).
“While our data suggest an unexpectedly high COVID-19 mortality rate of 34.6 percent among thoracic cancer patients, cancer as a whole cannot be generalized. Due to its comorbidities and tumour site, lung cancer may be different from others,” said Professor Marina Garassino of the National Tumour Institute in Milan, Italy. [Garassino MC, AACR 2020 Virtual Meeting I 2020] “What we don’t know is whether the incidence [of COVID-19] is also higher among these patients, and whether they are more susceptible to contracting the infection.”
In the absence of data regarding the susceptibility of cancer patients to COVID-19 infection but given the prevalence of severe outcomes among certain groups, crowded conditions at hospitals should be minimized, and telemedicine should be deployed wherever possible as should the use of oral agents or longer schedules of injectable drugs, advised Ascierto.
Data from Barlesi’s and Cai’s studies suggested that haematological malignancy is predictive of poor COVID-19 outcomes, while Barlesi’s and Zhang’s studies found this to be true for recent chemotherapy prior to COVID-19 diagnosis.
Notably, there was no consensus on the impact of cancer immunotherapy on COVID-19 infection. While Cai and colleagues found a significantly higher rate of severe outcomes in patients on immunotherapy vs other patient groups, Barlesi’s and Ascierto’s teams’ experience was different. “A controlled trial is needed to verify whether ICIs increase the risk of pneumonitis or if they are beneficial [in this population],” stated Ascierto.
“The full effect of the COVID-19 pandemic on cancer patients and cancer researchers has yet to become clear,” concluded Ribas.
As the field is evolving rapidly, the AACR will include sessions on COVID-19 and cancer in its Virtual Annual Meeting II to be held on 22–24 June. The AACR is also holding a dedicated meeting on COVID-19 and cancer in July.