key: cord-0839927-6x8e3qmk
authors: Luo, Jia; Rizvi, Hira; Preeshagul, Isabel R.; Egger, Jacklynn V.; Hoyos, David; Bandlamudi, Chaitanya; McCarthy, Caroline G.; Falcon, Christina J.; Schoenfeld, Adam J.; Arbour, Kathryn C.; Chaft, Jamie E.; Daly, Robert M.; Drilon, Alexander; Eng, Juliana; Iqbal, Afsheen; Lai, W. Victoria; Li, Bob T.; Lito, Piro; Namakydoust, Azadeh; Ng, Kenneth; Offin, Michael; Paik, Paul K.; Riely, Gregory J.; Rudin, Charles M.; Yu, Helena A.; Zauderer, Marjorie G.; Donoghue, Mark T.A.; Łuksza, Marta; Greenbaum, Benjamin D.; Kris, Mark G.; Hellmann, Matthew D.
title: COVID-19 in patients with lung cancer
date: 2020-06-17
journal: Ann Oncol
DOI: 10.1016/j.annonc.2020.06.007
sha: d6c5f76e4e32e14803113ebc625fb80d5c8dd9cf
doc_id: 839927
cord_uid: 6x8e3qmk

BACKGROUND: Patients with lung cancers may have disproportionately severe COVID-19 outcomes. Understanding the patient-specific and cancer-specific features that impact severity of COVID-19 may inform optimal cancer care during this pandemic. PATIENTS AND METHODS: We examined consecutive patients with lung cancer and confirmed diagnosis of COVID-19 (n=102) at a single center from March 12-May 6, 2020. Thresholds of severity were defined a priori as hospitalization, ICU/intubation/DNI (a composite metric of severe disease including ICU stay, intubation and invasive mechanical ventilation, and/or transition to do not intubate [DNI]), or death. Recovery was defined as >14 days from COVID-19 test and >3 days since symptom resolution. HLA alleles were inferred from MSK-IMPACT (n=46) and compared to controls with lung cancer and no known non-COVID-19 (n=5166). RESULTS: COVID-19 was severe in patients with lung cancer (62% hospitalized, 25% died). Although severe, COVID-19 accounted for a minority of overall lung cancer-deaths during the pandemic (11% overall). Determinants of COVID-19 severity were largely patient-specific features, including smoking status and chronic obstructive pulmonary disease (Odds ratios for severe COVID-19 2.9, 95% CI 1.07-9.44 comparing the median [23.5 pack-years] to never and 3.87, 95% CI 1.35-9.68, respectively). Cancer-specific features, including prior thoracic surgery/radiation and recent systemic therapies did not impact severity. HLA supertypes were generally similar in mild or severe cases of COVID-19 compared to non-COVID-19 controls. Most patients recovered from COVID-19, including 25% patients initially requiring intubation. Among hospitalized patients, hydroxychloroquine did not improve COVID-19 outcomes. CONCLUSION: COVID-19 is associated with high burden of severity in patients with lung cancer. Patient-specific features, rather than cancer-specific features or treatments, are the greatest determinants of severity.

National Cancer Institute (USA), The Lung Cancer Research Foundation, Genentech Roche, and PUMA Biotechnology for research conducted by Dr. Kris. MSK has licensed testing for EGFR T790M to MolecularMD. M.D.H. receives institutional research funding from Bristol-Myers Squibb; has been a compensated consultant for Merck, Bristol-Myers Squibb, AstraZeneca, Genentech/Roche, Nektar, Syndax, Mirati, Shattuck Labs, Immunai, Blueprint Medicines, Achilles, and Arcus; received travel support/honoraria from AstraZeneca, Eli Lilly, and Bristol-Myers Squibb; has options from Shattuck Labs, Immunai, and Arcus; has a patent filed by his institution related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from PGDx.

The remaining authors have no disclosures.

Original Article -COVID-19 in patients with lung cancers, J. Luo, H. Rizvi,…, M.D. Hellmann

Background: Patients with lung cancers may have disproportionately severe COVID-19 outcomes. Understanding the patient-specific and cancer-specific features that impact severity of COVID-19 may inform optimal cancer care during this pandemic.

We examined consecutive patients with lung cancer and confirmed diagnosis of COVID-19 (n=102) at a single center from March 12-May 6, 2020. Thresholds of severity were defined a priori as hospitalization, ICU/intubation/DNI (a composite metric of severe disease including ICU stay, intubation and invasive mechanical ventilation, and/or transition to do not intubate [DNI]), or death. Recovery was defined as >14 days from COVID-19 test and >3 days since symptom resolution.

HLA alleles were inferred from MSK-IMPACT (n=46) and compared to controls with lung cancer and no known non-COVID-19 (n=5166).

Results: COVID-19 was severe in patients with lung cancer (62% hospitalized, 25% died). Although severe, COVID-19 accounted for a minority of overall lung cancerdeaths during the pandemic (11% overall). Determinants of COVID-19 severity were largely patient-specific features, including smoking status and chronic obstructive pulmonary disease (Odds ratios for severe COVID-19 2.9, 95% CI 1.07-9.44 comparing the median [23.5 pack-years] to never and 3.87, 95% CI 1.35-9.68, respectively).

Cancer-specific features, including prior thoracic surgery/radiation and recent systemic therapies did not impact severity. HLA supertypes were generally similar in mild or severe cases of COVID-19 compared to non-COVID-19 controls. Most patients recovered from COVID-19, including 25% patients initially requiring intubation. Among hospitalized patients, hydroxychloroquine did not improve COVID-19 outcomes.

Conclusion: COVID-19 is associated with high burden of severity in patients with lung cancer. Patient-specific features, rather than cancer-specific features or treatments, are the greatest determinants of severity.

Original Article -COVID-19 in patients with lung cancers, J. Luo, H. Rizvi,…, M.D. Hellmann

Lung cancer, COVID-19, immunotherapy/ checkpoint blockade, chemotherapy, small molecule agents Highlights:

• COVID-19 is associated with high burden of severity in patients with lung cancer.

• Patient-specific features, rather than cancer-specific features or treatments, are the greatest determinants of severity.

Original Article -COVID-19 in patients with lung cancers, J. Luo, H. Rizvi,…, M.D. Hellmann

Patients with cancers, particularly those with lung cancers, have been reported by multiple series to have disproportionally increased severity outcomes from coronavirus disease 2019 (COVID-19), including higher rates of hospitalization and death [1] [2] [3] [4] . It is unknown whether lung cancer itself or other pre-existing factors such as age, genetic variation in immunity, smoking history, underlying cardiopulmonary disease, and/ or cancer-directed treatments predisposes an individual to significant symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We previously explored the impact of PD-1 blockade therapy on COVID-19 severity and did not find a clinically meaningful signal [5] . No population cohort to date has had sufficient detail and follow-up to address these issues or to characterize recovery from COVID-19. We hypothesized that a deeply annotated analysis of the experience of patients with lung cancers and COVID-19 from a single center in New York City, one of the epicenters of COVID-19 worldwide, would help address these ongoing issues to provide guidance and insight regarding both COVID-19 and cancer care in real-time during this pandemic.

This retrospective study was approved by the Institutional Review Board at Memorial Sloan Kettering Cancer Center (MSK) (protocol 20-142), which granted a waiver of informed consent.

Our study population included all patients with a diagnosis of lung cancer being treated at MSK who had a positive SARS-CoV-2 RT-PCR test between the first case identified on March 12, 2020 through May 6, 2020. Patients were followed through May 11, 2020.

We employed several data sources to identify patients including ICD diagnosis codes, pathology reports, institutional databases, and survey of physicians in the Thoracic Baseline laboratory values included complete blood count, serum creatinine, liver function tests, and inflammatory/ injury markers obtained on the day of the positive test.

If no blood tests were obtained on the date of the SARS-CoV-2 test, we used the value the day before or day after. Patients who were re-admitted for COVID-19 symptoms subsequent to their initial COVID-19 hospitalization were coded as a single hospitalization course. Extubation was defined as independence from invasive mechanical ventilator (iMV) support. Extracted results were entered into a clinical data form for subsequent analysis. To examine the association of HLA genotype with COVID-19 severity, we identified a control group using institutional databases to identify patients with lung cancers who were not known to have COVID-19 and who had MSK-IMPACT next generation sequencing in order to infer imputed class I HLA allele supertypes.

To examine the impact of cancer therapy on severity of COVID-19, we defined hospice (n=2) were included in the "hospitalization" analysis. Patients with unknown status for a given severity outcome (n=1 for ICU/intubation/DNI) were coded as unknown and removed from analysis for that outcome.

Recovered was defined as a combination of (a) 14 days-post negative swab per the institution standard and (b) at least three days since resolution of COVID-19 symptoms per CDC guidelines. Improving was defined as existence of a preponderance of evidence in the medical record (dates of disease course, notes, vital signs, and laboratory values) the patient was steadily improving with a trajectory toward recovery from COVID-19. The status of all other patients who had not died was categorized as pending.

Of the 102 patients, 46 had MSK-IMPACT next generation sequencing data to infer imputed HLA-A and HLA-B alleles. Each cohort's patients' HLA-A and B type were categorized into 12 supertypes, as previously defined using anchor residue specificity similarities [6] ; other HLA-A and B types that were not categorizable into one of these supertypes were included in a separate miscellaneous group called "Other A,B".

Patients were classified as having severe COVID-19 if they met criteria for ICU/intubation/DNI and/or died. All others were classified as having mild COVID-19.

Control HLA-A and HLA-B, data was available for 5166 patients with lung cancers and no known diagnosis of COVID-19, HLA-A and B types were categorized into supertypes as above. The control group was used to establish a null distribution. We examined if there were differences in the mild and severe cohorts as compared to the control group.

All comparisons were two-sided and Bonferroni corrected for multiple hypothesis testing.

Briefly, our pre-planned primary analysis was to evaluate the impact of baseline characteristics of interest on the severity and recovery of COVID-19 in patients with lung cancer. We used literature review of COVID-19 publications and directed acyclic graphs to identify relationships between baseline features of interest and examined features that may directly impact COVID-19 infection severity and recovery.

COVID-19 severity outcomes of interest were defined a priori as: hospitalization, death, and a composite metric of severe disease (ICU stay, intubation and invasive mechanical ventilation, and/or transition to DNI). We calculated odds ratios using a univariate logistic regression model to examine baseline characteristics and treatments that could affect COVID-19 severity. Logistic regression was chosen as the method of analysis because (a) our outcomes of interest were binary (e.g. death or not) rather than time to event and (b) we had prolonged follow up on patients (median 25 days), with the final status of COVID-19 in our patients known for 89%. Age, pack-years smoked, and BMI were treated as continuous variables. Given the plateauing effects of pack-years smoked, this variable was a priori log 10 transformed.

We performed descriptive statistics characterizing the disease course of COVID-19 in this population of patients with lung cancer. Survival and recovery analyses were estimated using the Kaplan-Meier method. For the survival analysis, patients were censored at the date of last contact prior to the end of the follow-up period. The recovery analysis was described by a cumulative incidence function with competing events being death and recovery from COVID-19. Fisher's exact test and the Mann Whitney U test were used to calculate p-values. All 95% confidence interval estimates reflect an alpha level of 0.025 in each tail. 95% confidence interval estimates for odds ratios were calculated using the Baptista-Pike method. Statistical analyses were performed using Python 3.7.3 using matplotlib, Prism 8.4.2 and R statistical software 3.6.2 using glm.

We identified 102 consecutive patients with lung cancers and a SARS-CoV-2 positive swab between March 12, 2020 and May 6, 2020 ( Table 1) . Patients were followed until May 11, 2020, inclusive of updated follow-up on patients previously reported [5] . Median follow-up was 25 days (interquartile range [IQR] 10-36 days). The median age was 68 years old (range 31-91 years old). Most patients had metastatic or active lung cancer (72%, n=73/102), and the median pack-year smoking history was 23.5 (range 0-120 pack-years). Common chronic conditions included hypertension (HTN, 56%, n=57/102) and chronic obstructive pulmonary disease (COPD, 24%, n= 24/102).

The patients who died from confirmed COVID-19 during the follow-up period represented 11% of all deaths among patients with lung cancers at our institution. The peak percent of deaths related to COVID-19 was approximately 20% in April 2020 ( Figure 1A) . Most deaths occurred within a week of COVID-19 diagnosis; an estimated 85% (95% confidence interval [CI] 78%-92%), 81% (95% CI 73%-89%), and 78% (95% CI 70-87%) of patients were alive at 1, 2, and 4 weeks, respectively ( Figure 1B) .

Although symptoms such as cough (70%) and fever (59%) were common, the constellation of symptoms within a given patient at presentation were variable ( Figure   1C ). Of 102 patients, 62% (63/102) required hospital admission and 25% died (25/102) ( Figure 1D ). Of the patients who required ICU level of care (21%, n=21), 14% recovered and 72% died.

Among patients with lung cancers, several baseline clinical features consistently associated with increased risk of COVID-19 severity, including age, smoking history, COPD, and hypertension (Figure 2A, 2B) . Congestive heart failure (CHF) associated with increased risk of COVID-19 severity, although baseline CHF was present in a small number of patients in this analysis (n=7). Cancer-specific features, such as presence of active/metastatic lung cancer or history of prior thoracic radiation or thoracic surgery did not appear to impact severity of COVID-19. Histology, presence of targetable oncogenes, or PD-L1 immunohistochemistry expression also did not impact severity (Supplementary Figure 1A) .

Among hospitalized patients, the need for supplemental oxygen at presentation associated with increased odds of severe COVID-19 illness (OR 9.0, 95% CI 2.31-28.44 for ICU admission, intubation, and/or change to DNI status to avoid intensification of care [ICU/intubation/DNI] and OR 4.21, 95% CI 0.99-15.25 for death) (Figure 2B) .

Elevated creatinine at initial presentation associated with increased severity (p=0.002 for ICU/intubation/DNI; p=0.002 for death) (Figure 2C) . Levels of inflammatory markers at presentation were generally elevated in patients who developed more severe COVID-19 ( Figure 2C) . Other laboratory results at presentation, such as white blood cell count, absolute lymphocyte count, and liver function tests did not differentiate severity of COVID-19 (Supplementary Figure 1B) .

As the adaptive immune response to SARS-CoV-2 antigens may be relevant for determining severity of COVID-19 [7] , we examined the association between HLA-A and HLA-B alleles on outcomes. Imputation of HLA-A and HLA-B alleles were available in 46 of 102 (45%) patients with lung cancers and known COVID-19 and were organized into twelve HLA supertypes based on similarity of antigen presentation [6] . Patients with mild (n=29, no ICU/intubation/DNI or death) or severe (n=17, ICU/intubation/DNI or death) disease were compared to the control cohort of 5166 patients with lung cancers and no known COVID-19. Generally, the frequency of HLA-A and HLA-B alleles were similar in mild and severe COVID-19 cases compared to controls (Figure 2D) . Although HLA-B44 supertype was numerically more common among patients with severe COVID-19, this was not significant after adjustment for multiple hypothesis testing.

We examined the impact of cancer therapy on the severity of COVID-19, a particularly critical question to guide real-time cancer care during this pandemic. Similar to our previous results [5] , recent PD-1 blockade with or without chemotherapy did not associate with increased severity of COVID-19 (Figure 3A-B) . We did not observe a consistent impact of severity in patients who recently received chemotherapy or tyrosine kinase inhibitors (TKIs) (Figure 3C-D) .

Although the rates of severe COVID-19 appear to be increased in patients with lung cancers, recovery occurs in the majority of patients (65% patients recovered or were improving as of this writing). As expected, the rates and timing of recovery associated with the highest level of care during the disease course (3-week recovery rate in outpatients, 60%, 95% CI 43%-77%; in patients requiring non-ICU hospitalization, 20%, 95% CI 8%-33%; in patients requiring ICU care, 5%, 95% CI 0%-15%) (Figure 4A) Similar to what has been described in the literature [1, 8] , the disease course of COVID-19 is more severe in patients with lung cancers. Although COVID-19 led to death in approximately a quarter of patients with lung cancer, COVID-19 represented a minority of the deaths among patients with lung cancers that occurred during this period. This finding amplifies the importance of maintaining urgent focus on the needs of patients with cancer and optimizing cancer care within the context of the local prevalence of SARS-CoV-2 infection [9] .

The course of SARS-CoV-2 infection in lung cancer was longer and more severe than what has been reported in the general US population [10] [11] [12] . About a third of patients experienced a milder outpatient course, two thirds needed hospitalization, and a quarter of patients died. Although more frequently severe, these observations mirror common phenotypes of COVID-19 illness reported in the literature for the general population [13, 14] -a mild and/or asymptomatic outpatient course; a rapid and fatal presentation; and a subacute lingering course that generally leads to recovery.

The diversity of these COVID-19 phenotypes is undoubtedly in part related to underlying clinical features, such as smoking history, age, hypertension, and chronic obstructive pulmonary disease (COPD) as seen in our report. Recent reports, including a cohort of patients with thoracic cancers mostly from epicenters in Europe with somewhat differing health care resources (33% death rate, but 8.3% ICU admission, 5% rate of intubation), A limitation of our study was the sample size, which impacts the ability to perform adjustments for multiple potential confounders (such as effect modifiers and confounders by indication) with smaller effect sizes. Larger sample sizes and cohorts are needed to confirm the generalizability of our results.

Our results characterize COVID-19 in patients with lung cancers, highlighting both the urgent vulnerability of patients with lung cancer during this pandemic as well as the persistently critical need to continue, and drive improvements in, optimal cancer care. * denominators reflect available data; unless specified, unknowns are not included; (a) metastatic or active lung cancer was defined as patients with metastatic lung cancer or patients undergoing active treatment for lung cancer (e.g. neoadjuvant or adjuvant therapy); (b) COPD was defined as anyone with this diagnosis listed as a part of the past medical history plus either an abnormal pulmonary function test interpreted as consistent with COPD or had inhalers for COPD listed in the outpatient medication record. Patients with only radiologic evidence of COPD or a note in the medical record the diagnosis was in question were not included; (c) Non-COPD lung disease was defined as underlying lung disease other than COPD (e.g. reactive airways disease, pneumonitis, abnormal pulmonary function test interpreted as underlying lung disease, etc.); (d) Congestive heart failure was defined as anyone with NYHA functional class I-IV disease. As such, anyone with this diagnosis listed as a part of the past medical history or an abnormal cardiac echocardiogram demonstrating evidence of structural heart disease consistent with this diagnosis was included; (e) An additional 4 patients received intubation and invasive mechanical ventilation and subsequently elected not to receive further necessary intensification of care or interventions. 

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Original Article -COVID-19 in patients with lung cancers

The authors thank Pranay Sinha and Jean W. Liew for helpful discussions related to this analysis.

cancer specific characteristics