key: cord-0958864-93oiiqqi authors: Tagliamento, Marco; Spagnolo, Francesco; Poggio, Francesca; Soldato, Davide; Conte, Benedetta; Ruelle, Tommaso; Barisione, Emanuela; De Maria, Andrea; Del Mastro, Lucia; Di Maio, Massimo; Lambertini, Matteo title: Italian survey on managing immune checkpoint inhibitors in oncology during COVID‐19 outbreak date: 2020-06-14 journal: Eur J Clin Invest DOI: 10.1111/eci.13315 sha: 14f91b67f34e3ac4aaa752a2bb34caa5c5f0ef68 doc_id: 958864 cord_uid: 93oiiqqi BACKGROUND: During COVID‐19 outbreak, oncological care has been reorganized. Cancer patients have been reported to experience a more severe COVID‐19 syndrome; moreover, there are concerns of an interference between immune checkpoint inhibitors (ICIs) and SARS‐CoV‐2 pathogenesis. MATERIALS AND METHODS: Between May 6 and 16, 2020, a 22‐item survey was sent to Italian physicians involved in administering ICIs. It aimed to explore the perception about SARS‐CoV‐2 related risks in cancer patients receiving ICIs, and the attitudes towards their management. RESULTS: The 104 respondents had a median age of 35.5 years, 58.7% were females and 71.2% worked in Northern Italy. 47.1% of respondents argued a synergism between ICIs and SARS‐CoV‐2 pathogenesis leading to worse outcomes, but 97.1% would not deny an ICI only for the risk of infection. During COVID‐19 outbreak, to reduce hospital visits, 55.8% and 30.8% opted for the highest labeled dose of each ICI (55.8%) and/or, among different ICIs for the same indication, for the one with the longer interval between cycles, respectively. 53.8% of respondents suggested testing for SARS‐CoV‐2 every cancer patient candidate to ICIs. 71.2% declared to manage patients with onset of dyspnea and cough as SARS‐CoV‐2 infected until otherwise proven; however, 96.2% did not reduce the use of steroids to manage immune‐related toxicities. The administration of ICIs in specific situations for different cancer types has not been drastically conditioned. CONCLUSIONS: These results highlight the confusion around the perception of a potential interference between ICIs and COVID‐19, supporting the need of focused studies on this topic. Coronavirus disease 2019 outbreak has led to the reorganization of national health systems in many specialties including medical oncology. 1, 2 Infections by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is responsible for a wide range of clinical conditions. 3, 4 Independent risk factors for infection and development of severe events are older age and preexisting comorbidities. 5, 6 Cancer patients have been also reported to be at potential higher risk of complications and death, particularly if immunosuppressive drugs are administered close to the time of infection. 7, 8 The host immune system is crucial in determining the clinical course of COVID-19. 9 It is implicated into the clearance of the virus when effective, and in disease propagation when deficient. 10 The severity of COVID-19 is caused not only by direct viral damage, but also by an impaired immune host reaction, sometimes resulting in an extremely strong inflammatory response leading to airways damage and life-threating acute respiratory distress syndrome. 9 A cytokine release syndrome (CRS) seems to be responsible for the most severe conditions. 10, 11 Immune checkpoint inhibitors (ICIs) constitute a crucial drug class for the treatment of many cancer types in different settings. 12 Negative checkpoint blockade removes the inhibition on T-cell activation, driving effective long-lasting antitumor response through central and peripheral immune mechanisms. 13, 14 Whether and how ICIs can interfere with the physiopathology of SARS-CoV-2 infection is still matter of discussion. This interaction may worsen the hyperinflammation with CRS observed in severe cases of COVID-19, but the antagonism of checkpoint axis like PD-1/PD-L1 could also potentially participate in accelerating the resolution of viral infection. 15, 16 Beyond this complexity, SARS-CoV-2 infection in cancer patients poses also issues related to differential diagnosis between cancer-related symptoms or immune related adverse events (irAEs) and COVID-19 manifestations. 17 Despite immunotherapy cannot be considered immunosuppressive per se, a special consideration when referring to the risk of SARS-CoV-2 infections should be given to patients treated with long course of corticosteroids for irAEs after or during treatment with ICIs. 18 First reports assessing the impact of ICIs on clinical outcomes of cancer patients with SARS-CoV-2 infection produced contrasting results. [19] [20] [21] [22] Here we present the results of a survey conducted among Italian physicians involved in the administration of ICIs in oncology to explore their perception about SARS-CoV-2 related risks in This article is protected by copyright. All rights reserved cancer patients receiving these therapies, and the attitudes towards their management during COVID-19 outbreak. An anonymous 22-item questionnaire was shared on May 6, 2020 on a social media platform created during COVID-19 pandemic with private access dedicated to Italian physicians involved in cancer care. The link to fill the survey remained active until May 16, 2020. Respondents had to answer all the questions in order to send the survey. Reporting of the study conforms to broad EQUATOR guideline. 23 The objectives of this survey were to examine the impact of COVID-19 outbreak on the perception of Italian physicians involved in the administration of ICIs about SARS-CoV-2 related risks in cancer patients receiving these therapies, and their attitudes towards the management of ICIs in oncology. We also investigated how COVID-19 outbreak has modified the approach of respondents in specific clinical settings. This article is protected by copyright. All rights reserved Considering the descriptive nature of the study, a pre-planned sample size was not established. However, estimating a target population of around 1,300 physicians who could have access to the survey, we aimed to reach at least 100 responses to have a margin of error less than 10% with a 95% confidence level. Characteristics of responding physicians were analyzed using descriptive statistics, and results were reported as percentage of respondents to each answer on the total number of people filling the survey or dealing with a particular cancer disease. Complete results are displayed in Supplement 2. The survey reached around 1,300 physicians involved in cancer care. A total of 104 physicians dealing with the administration of ICIs for treating cancer patients answered the questionnaire. A total of 39.4% (n=41) of respondents did not feel confident to give an opinion on whether an interference between the activity of ICIs and the pathogenesis of SARS-CoV-2 infection exists; 35.6% (n=37) believed that the activity of ICIs may interfere with the pathogenesis of SARS-CoV-2 infection, while 25% (n=26) did not ( Figure 1A ). The perception of respondents regarding the potential increased risk of severe events related to SARS-CoV-2 infection in cancer patients treated with ICIs is displayed in Figure 1B . A total of 47.1% (n=49) of respondents agreed on these concerns, while 14.4% (n=15) and 38.5% (n=40) did not or did not know, respectively. This article is protected by copyright. All rights reserved The vast majority of respondents (n=101, 97.1%) would not deny an ICI to a patient with cancer during COVID-19 pandemic only based on the potential eventuality of infection by SARS-CoV-2. Two clinical situations were explored to assess the issues related to the differential diagnosis between irAEs and COVID-19 manifestations in cancer patients treated with ICIs: A) how to manage a patient with onset of dyspnea and cough ( Figure 4A) ; B) how to manage a patient whit onset of diarrhea ( Figure 4B) . This article is protected by copyright. All rights reserved A total of 96.2% (n=100) of respondents did not modify the attitude in administering corticosteroids to treat irAEs during COVID-19 outbreak. Lung cancer Prescription of durvalumab as maintenance therapy after chemo-radiotherapy for unresectable locally advanced non-small cell lung cancer (NSCLC) with PD-L1 expression ≥1% was assessed. Among the 53 respondents who declared to deal with lung cancer in their practice, 49 (92.5%) stated to have not reduced its use in this setting. Prescription of pembrolizumab as a combination treatment with a platinum-based doublet with pemetrexed as first-line for metastatic non-squamous NSCLC with PD-L1 expression <50% (negative for EGFR and ALK) was then explored. A total of 47 (85.5%) respondents did not reduce its use in clinical practice. The use of ICIs in the adjuvant setting for patients with stage III melanoma older than 75 years was investigated. Among the 35 respondents who declared to deal with melanoma in their practice, 8 (22.9%) declared to have renounced to the prescription of ICIs in a limited number of cases. On the contrary, 27 (77.1%) respondents did not modify the indication for ICIs in this setting ( Figure 5 ). The use of atezolizumab as first-line treatment in combination with nab-paclitaxel for PD-L1positive triple-negative advanced breast cancer was investigated (notably, this regimen is not reimbursed by Italian health system, but is currently accessible through a compassionate use program). Among the 47 respondents who declared to deal with breast cancer in their practice, 43 (91.5%) did not reduce the use of this drug. The use of pembrolizumab as second-line treatment for patients with advanced bladder carcinoma progressing on platinum-based chemotherapy was explored. Among the 57 respondents who This article is protected by copyright. All rights reserved declared to deal with bladder cancer in their practice, 91.2% (n=52) did not reduce its use in this setting. The choose of nivolumab as second-line therapy for patients with advanced kidney cancer progressing on a tyrosine kinase inhibitor was assessed. Among the 60 respondents who declared to deal with kidney cancer in their practice, 57 (95%) stated to have not reduced its use in this setting. Since the first reported cases of SARS-CoV-2 infection in cancer patients, some concerns have been raised on whether and how ICIs could interfere with the pathogenesis of the virus worsening the hyperinflammation with CRS, thus if receiving or having received an ICI should be considered as an independent negative prognostic factor for the outcome of SARS-CoV-2 infection. 17 Moreover, besides the overlapping between cancer-related signs/symptoms or side effects of oncological treatments (including irAEs) and COVID-19 manifestations, additional issues could emerge from the differential diagnosis between radiological findings of lung involvement from SARS-CoV-2 and pneumonitis induced by ICIs. 9, 24 To the best of our knowledge, this is the first study exploring the perception of physicians towards these unsolved issues, and whether the outbreak has modified the clinical practice in managing the treatment with ICIs in oncology. The perception of Italian physicians involved in the administration of ICIs concerning a possible interference between the activity of ICIs and the pathogenesis of SARS-CoV-2 was diversified. Almost 40% of respondents was not confident to give an answer, while 35.6% reported that an interaction may exists. This uncertainty is likely due to the lack of univocal evidences on this regard. [19] [20] [21] [22] Furthermore, 47.1% of respondents supported the hypothesis of a synergism between the mechanism of action of ICIs and the pathogenesis of SARS-CoV-2 infections, thus being worried about the potential higher risks of COVID-19 related complications in this patient population. Nevertheless, it is comforting that 97.1% of respondents would not deny ICIs as a treatment option at the time of COVID-19 outbreak only based on the possible risks of infection This article is protected by copyright. All rights reserved by SARS-CoV-2, considering that so far a clear evidence of a detrimental effect of its administration is still lacking. While it is essential to ensure the best care to cancer patients during the current health emergency, also by giving access to ICIs that have demonstrated clinically relevant results in terms of efficacy, it is also advisable to find strategies to reduce the risk of SARS-CoV-2 infections. The European Society for Medical Oncology (ESMO) has created dedicated recommendations for the management of various aspects of oncological care, in order to mitigate the negative impact of COVID-19 outbreak on cancer patients. 25 Only 31.7% of respondents did not modify the choice of the ICI and the schedule of administration in order to reduce the number of hospital visits. Currently, the preference for the higher flat-dose of an ICI as single agent, whenever allowed, is supported by evidences of comparable safety and efficacy between different schedules. 26,27 Reducing the number of hospital visits while maintaining treatment effect is a reasonable safety measure that should be taken into account during COVID-19 outbreak. For patients beginning the treatment, the choice for an ICI rather than another with a different interval between the administrations, if in indication in the same setting, should be done on a case by case evaluation on the basis of available efficacy and safety data in that setting of disease. Testing cancer patients for SARS-CoV-2, with the aim to identify and isolate also asymptomatic carriers, is a strategy for the control of the contagion that has already been claimed. 28, 29 This perception finds a confirmation in our survey, in which 53.8% of respondents supported this approach before starting treatment with ICIs. The overlapping between clinical manifestations of irAEs and COVID-19, and the consequent management, is an additional concern. While immune related pneumonitis is not so frequent in cancer patients treated with ICIs (1-5% with anti-CTLA-4 or anti PD-1/PD-L1 as monotherapy, 5-10% with combination strategies), 30, 31 it enters in the differential diagnosis list at the time of COVID-19 outbreak for the 71.2% of respondents. On the contrary, diarrhea is one of the most frequent irAE, 32 and despite its overall rate is 10.4% in patients with COVID-19 in a pooled analysis, only 28.8% of respondents reported to manage a patient with colitis as a SARS-CoV-2 infected patient until otherwise proven, potentially leading to a risk of contagion in the case of underlying infection by SARS-CoV-2. 33, 34 Having dedicated facilities where cancer patients could This article is protected by copyright. All rights reserved be managed also in the case of suspected SARS-CoV-2 infection should be considered of high priority in order to continue providing the needed care in the safest possible environment. 35 The 96.2% of respondents did not modify the use of corticosteroids for the treatment of irAEs. Notably, its use has also been associated with a reduction in the risk of death in patients with COVID-19 related pneumonia. 36 Hence, whenever needed, corticosteroids for managing irAEs should not be denied. The integration of ICIs in oncology has been associated with improved progression-free and overall survival in different cancer types and settings, including lung cancer, 37,38 melanoma, 39, 40 triple-negative breast cancer, 41 urothelial cancer, 42 and renal cell carcinoma. 43 The results of our survey do not demonstrate a significant change in the attitudes of Italian physicians towards the prescription of ICIs during COVID-19 outbreak. However, we observed that 22.9% of respondents dedicated to the treatment of melanoma declared to have reduced its use in the adjuvant setting for stage III elderly patients. These data, probably driven by the higher risk of COVID-19 severe events in the elderly population, deserve a reflection considering the significant benefit associated with ICIs in this setting. 39, 40 LIMITATIONS This study has some limitations, mainly derived by the relatively small number of respondents. Nevertheless, it gives a representative picture of the perception of physicians dealing with SARS-CoV-2 related issues towards the management of ICIs in oncology during COVID-19 outbreak, as the majority of respondents work in the most affected area of Italy (ie, the north). Another limitation is that we have explored the attitudes of Italian physicians towards the use of ICIs in limited and specific clinical conditions. However, we believe that these were the situations in which the role of ICIs could be questioned in such a health emergency. Reorganization of a large academic hospital to face COVID-19 outbreak: The model of Parma Cancer care during the spread of coronavirus disease 2019 (COVID-19) in Italy: young oncologists' perspective Critical Care Utilization for the COVID-19 Outbreak in Early Experience and Forecast During an Emergency Response Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis Does comorbidity increase the risk of patients with COVID-19: evidence from meta-analysis Clinical characteristics of COVID-19-infected cancer patients: A retrospective case study in three hospitals within Wuhan, China. Ann Oncol Patients with cancer appear more vulnerable to SARS-COV-2: a multi-center study during the COVID-19 outbreak. Cancer Discov Coronavirus Disease 2019 (COVID-19) and Immune-Engaging Cancer Treatment The trinity of COVID-19: immunity, inflammation and intervention Accepted Article This article is protected by copyright. All rights reserved 11 COVID-19 infection: the perspectives on immune responses New emerging targets in cancer immunotherapy beyond CTLA-4, PD-1 and PD-L1: Introducing an "ESMO Open -Cancer Horizons Cancer immunotherapy using checkpoint blockade Fundamental Mechanisms of Immune Checkpoint Blockade Therapy Cytokine release syndrome in severe COVID-19 The PD-1/PD-L1 Axis and Virus Infections: A Delicate Balance Controversies about COVID-19 and anticancer treatment with immune checkpoint inhibitors Do checkpoint inhibitors compromise the cancer patients' immunity and increase the vulnerability to COVID-19 infection? Immunotherapy blockade on severity of COVID-19 in patients with lung cancers Outcome of cancer patients infected with COVID-19, including toxicity of cancer treatments Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study. The Lancet COVID-19 mortality in patients with cancer on chemotherapy or other anticancer treatments: a prospective cohort study. The Lancet A catalogue of reporting guidelines for health research Challenges in lung cancer therapy during the COVID-19 pandemic Cancer guidelines during the COVID-19 pandemic Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation SARS-CoV-2 Transmission in Patients With Cancer at a Tertiary Care Hospital in Wuhan, China Risk of Pneumonitis and Pneumonia Associated With Immune Checkpoint Inhibitors for Solid Tumors: A Systematic Review and Meta-Analysis Treatment-Related Adverse Events of PD-1 and PD-L1 Inhibitors in Clinical Trials: A Systematic Review and Meta-analysis Gastrointestinal and Hepatic Toxicities of Checkpoint Inhibitors: Algorithms for Management COVID-19: focus on the lungs but do not forget the gastrointestinal tract infection: pathogenesis, epidemiology, prevention and management Accepted Article This article is protected by copyright. All rights reserved 35 Call for ensuring cancer care continuity during COVID-19 pandemic Use of Corticosteroids in Coronavirus Disease 2019 Pneumonia: A Systematic Review of the Literature Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer Three-Year Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC-Update from PACIFIC Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma Adjuvant nivolumab (NIVO) versus ipilimumab (IPI) in resected stage III/IV melanoma: 3-year efficacy and biomarker results from the phase III CheckMate 238 trial Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of >2 years of follow-up Final analysis of the CheckMate 025 trial comparing nivolumab (NIVO) versus everolimus (EVE) with >5 years of follow-up in patients with advanced renal cell carcinoma (aRCC)