TYPE Original Research PUBLISHED 22 August 2022 DOI 10.3389/fmed.2022.891179 Incidence and characteristics of OPEN ACCESS adverse drug reactions in a cohort of patients treated with EDITED BY Yu Luo, Shanghai University of Engineering Sciences, China REVIEWED BY PD-1/PD-L1 inhibitors in Fernando Martínez Valle, Universitat Autònoma de Barcelona, Spain real-world practice Haitao Sun, Fudan University, China Mònica Sabaté Gallego1,2*, Eulàlia Pérez Esquirol1 , *CORRESPONDENCE Mònica Sabaté Gallego Núria Garcia Doladé3 , Xavier Vidal Guitart1,2 , monica.sabate@vallhebron.cat Maria-Josep Carreras Soler4 , Anna Farriols Danés4 , SPECIALTY SECTION This article was submitted to Enriqueta Felip5,6 , Irene Braña5,6 , Joan Carles Galceran5,6 , Translational Medicine, a section of the journal Rafael Morales Barrera5,6 , Eva Muñoz-Couselo5,6 and Frontiers in Medicine Antònia Agustí Escasany1,2 RECEIVED 07 March 2022 1 Clinical Pharmacology Service, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain, ACCEPTED 03 August 2022 2 Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona, PUBLISHED 22 August 2022 Bellaterra, Barcelona, Spain, 3 Catalan Institute of Pharmacology Foundation, Vall d’Hebron CITATION Barcelona Hospital Campus, Barcelona, Spain, 4 Pharmacy Service, Vall d’Hebron Barcelona Hospital Sabaté Gallego M, Pérez Esquirol E, Campus, Barcelona, Spain, 5 Clinical Oncology Service, Vall d’Hebron Barcelona Hospital Campus, Garcia Doladé N, Vidal Guitart X, Barcelona, Spain, 6 Vall d’Hebron Institute of Oncology, Vall d’Hebron Barcelona Hospital Campus, Carreras Soler M-J, Farriols Danés A, Barcelona, Spain Felip E, Braña I, Carles Galceran J, Morales Barrera R, Muñoz-Couselo E and Agustí Escasany A (2022) Incidence and characteristics of Background: Data related to adverse drug reactions (ADRs), specifically adverse drug reactions in a cohort of immune-related adverse events (irAEs), in long-term treatment with patients treated with PD-1/PD-L1 immunotherapy in real-world practice is scarce, as is general information inhibitors in real-world practice. Front. Med. 9:891179. regarding the management of ADRs. doi: 10.3389/fmed.2022.891179 Objectives: To characterize and describe the incidence of ADRs in patients COPYRIGHT who began immunotherapy treatment in clinical practice. © 2022 Sabaté Gallego, Pérez Esquirol, Garcia Doladé, Vidal Guitart, Carreras Methods: In a prospective observational study cancer patients ≥18 years of Soler, Farriols Danés, Felip, Braña, age who were treated with a monotherapy regime of PD-1/PD-L1 inhibitors Carles Galceran, Morales Barrera, Muñoz-Couselo and Agustí Escasany. were evaluated. The study period was from November 2017 to June 2019 and This is an open-access article patients were followed up until June 2021. Patients were contacted monthly distributed under the terms of the Creative Commons Attribution License by telephone and their electronic health records were reviewed. Each ADR (CC BY). The use, distribution or was graded according to the Common Terminology Criteria for Adverse Events reproduction in other forums is (CTCAE 5.0). permitted, provided the original author(s) and the copyright owner(s) Results: Out of 99 patients, 86 met the inclusion criteria. Most were male are credited and that the original publication in this journal is cited, in (67.4%), with a median age of 66 (interquartile range, IQR: 59–76). The most accordance with accepted academic frequent cancer was non-small cellular lung cancer (46 cases, 53.5%), followed practice. No use, distribution or by melanoma (22, 25.6%). A total of 74 patients (86%) were treated with reproduction is permitted which does not comply with these terms. anti-PD-1 drugs and 12 (14%) were treated with anti-PD-L1 drugs. The median treatment durations were 4.9 (IQR: 1.9–17.0) and 5.9 months (IQR: 1.2–12.3), respectively. Sixty-three patients (73%) developed from a total of 156 (44% of the total number of ADR) irADRs, wherein the most frequent were skin disorders (50 cases, 32%, incidence = 30.5 irADRs/100 patients per year [p-y]), gastrointestinal disorders (29, 19%, 17.7 irADRs/100 p-y), musculoskeletal Frontiers in Medicine 01 frontiersin.org Sabaté Gallego et al. 10.3389/fmed.2022.891179 disorders (17, 11%, 10.4 irADRs/100 p-y), and endocrine disorders (14, 9%, 8.6 irADRs/100 p-y). A total of 22 irADRs (14%) had a latency period of ≥12 months. Twelve irADRs (7.7%) were categorized as grade 3–4, and while 2 (1.3%) were categorized as grade 5 (death). Sixty-one irADRs (39.1%) in 36 patients required pharmacological treatment and 47 irADRs (30.1%) in 22 patients required treatment with corticosteriods. Conclusion: The majority of patients treated with anti-PD1/PDL1-based immunotherapy experienced adverse reactions. Although most of these reactions were mild, 11.5% were categorized as grade 3 or above. A high percentage of the reactions were immune-related and occurred throughout the treatment, thereby indicating that early identification and close monitoring is essential. KEYWORDS immunotherapy, adverse reaction, immune-related adverse reaction, pharmacovigilance, real-world practice Introduction adverse effects related to organ-specific immune mechanisms have been described, including colitis, hepatitis, pneumonitis, Since their initial approval by the European Medicines and hypothyroidism, as well as general adverse events related to Agency (EMA), the use of immunotherapy drugs in different immune activation, including fatigue, diarrhoea, and dermatitis. cancer indications has increased gradually. As such, there Other less frequent adverse effects potentially attributable to is a requirement to detect the occurrence of adverse drug immune mechanisms, such as musculoskeletal problems or reactions (ADRs), and in particular, immune-related adverse neurologic alterations, have also been described in patients events (irAEs), when these treatments are used over a prolonged treated with immunotherapy. Although the real frequency of period of time in real-world clinical practice. these rare adverse effects is not known, they may negatively Immune checkpoint inhibitors (CPIs), such as the impact a patient’s quality of life, and so a better understanding cytotoxic T lymphocyte associated antigen-4 (CTLA-4) of irAEs is necessary to determine the risk–benefit ratio for each antibody ipilimumab and the programmed cell death (PD- patient when prescribing anti-PD-1/PD-L1 drugs (5). 1)/programmed cell death ligand-1 (PD-L1) antibodies Moreover, since treatment with anti-PD-1 or anti-PD-L1 nivolumab, pembrolizumab, and atezolizumab, were the first therapies can require months or years to complete, it is also drugs approved for use in immunotherapy to treat cancer (1–3). important to know the frequency of such adverse effects over More specifically, in May 2017, nivolumab and pembrolizumab the duration of treatment. Although these effects could appear were approved for some indications, such as advanced at any time during treatment, it has been reported that those melanoma, non-small cell lung cancer, Hodgkin’s lymphoma, related to skin, gastrointestinal, and hepatic reactions tend to and bladder urothelial cancer. Later, these antibodies were also appear earlier than those related to the pulmonary, endocrine, approved for renal cell carcinoma and squamous head and and renal systems (6). Given that such information is scarce, neck cancers. In addition, atezolizumab, which was initially physicians should be aware of how to manage patients who suffer approved for non-small cell lung cancer and bladder urothelial from irAEs during treatment. Indeed, despite the relatively low cancer, was also later approved for additional indications, rates of high-grade side effects with these treatments (usually namely small cell lung cancer, triple-negative breast cancer, ∼10%), some can be life-threatening and require urgent and and hepatocellular carcinoma. The treatment of other types appropriate management (7). In addition, since immunotherapy of cancer by anti-PD-1/PD-L1 drugs alone, or in combination treatment is being gradually expanded to patients with earlier- with immunotherapeutic and non-immunotherapeutic drugs, stage cancer and thus, longer life expectancies, the collection of has also been approved more recently (4). such information becomes paramount (8). Due to the fact that immunotherapy treatment stimulates Currently, the available information related to the the natural immune defence against cancer cells, its adverse management of immune toxicity is obtained from the effects are related to immune responses of normal cells. meta-analysis of randomised clinical trials and from Although anti-PD-1 drugs are overall less toxic than other observational retrospective studies or case reports, but oncologic treatments, such as standard chemotherapy, irAEs prospective information on the detection and management of have been described in several clinical trials. For example, the toxicity is lacking (4, 9, 10). Frontiers in Medicine 02 frontiersin.org Sabaté Gallego et al. 10.3389/fmed.2022.891179 FIGURE 1 Flow chart of patients starting immune checkpoint inhibitors (ICI). *PD, progression disease; PR, partial response; NED, no-evidence disease; ADR, adverse drug reaction. **ADR was the only reason for ending treatment in 6 patients: adrenal insufficiency and cholestatic liver injury (1), acute renal insufficiency (1), interstitial pneumonitis (1), bipulmonary infiltrates (1), hypopituitarism (1), autoimmune colitis and cytomegalovirus gastrointestinal infection (1). In 5 patients there were additional reasons: pruritus and PD (1), adrenal insufficiency and PD (1), hyperamylasaemia and NED (1), dermatitis psoriasiform and rash and PR (1) and diarrhoea and PR (1). Other reasons of ending ICI treatment were appendicitis (1 patient), ictus (1), patient withdraw consent at the third visit (1), cognitive impairment identified at the second visit (1). The aim of our study is therefore to characterise and the study was commenced, an amendment was made to the describe the incidence of adverse reactions occurring in patients protocol, and patients treated with atezolizumab were included. who began immunotherapy treatment in clinical practice at Other indications were also added to the protocol at this point, our institution, specifically focusing on those who underwent including squamous cell head and neck cancers, and urothelial treatment with an anti-PD1/PDL1 monotherapy and focusing carcinoma (advanced or metastatic). Patients treated with other on the frequency of irADRs. immunotherapy drugs or with a combination of such drugs were excluded, as were those participating in clinical trials. Materials and methods Data sources This prospective observational study evaluated cancer patients who were consecutively treated in real-world practice Patients were identified using the daily treatment list with monotherapy of PD-1/PD-L1 checkpoint inhibitors of the pharmacy service and were included after signing (standard schedules) from November 2017 to June 2019, and documenting their informed consent. Each patient was wherein patient follow-up was continued until June 2021, contacted monthly by telephone and was interviewed in regardless of the treatment line employed. The patients relation to the occurrence of adverse reactions. A structured were followed until treatment interruption or until the questionnaire was employed for this purpose. The monthly end of the study. The study was conducted at the Vall telephone interview carried out to obtain information related d’Hebron University Hospital (Catalunya, Spain) and the study to any adverse effects began with an open question, followed protocol was approved by the Ethical Committee of the same by some symptom-focused questions (e.g., related to organ- hospital (16/6/2017). specific irADRs, including colitis, hepatitis, pneumonitis, and The inclusion criteria included patients ≥18 years of age who hypothyroidism, as well as more general adverse reactions began treatment with nivolumab or pembrolizumab following related to immune activation, including fatigue, diarrhoea, a diagnosis of metastatic non-small cell lung cancer, advanced and dermatitis). To obtain further information, the patient’s melanoma, or advanced renal cancer. Eight months after electronic health record and laboratory test results (i.e., the Frontiers in Medicine 03 frontiersin.org Sabaté Gallego et al. 10.3389/fmed.2022.891179 TABLE 1 General characteristics of patients. Included patients, n (%) NSCLC Melanoma Head and neck Renovesical Total 46 (53.5) 22 (25.6) 9 (10.5) 9 (10.5) 86 (100) Age, median (IQR) (min-max), years 66.5 (60–72) (41–87) 74 (63–80) (39–88) 57 (54–62) (50–65) 72 (58–78) (38–85) 66 (59–76) (38–88) Gender, male/female, n (%) 30 (65.2)/16 (34.8) 12 (54.5)/10 (45.5) 8 (88.9)/1 (11.1) 8 (88.9)/1 (11.1) 58 (67.4)/28 (32.6) Charlson CIS, median (IQR) (min-max) 5 (3–8) (2–14) 4 (2–6) (2–11) 3 (2–4) (2–5) 6 (3–8) (2–14) 4 (2–6) (2–14) ◦ Treatment, 1st L / 2 n L or more, n (%) 7 (15.2)/39 (84.8) 17 (77.3)/5 (22.7) 3 (33.3)/6 (66.7) 0/9 (100) 27 (31.4)/59 (68.6) Anti-PD-1 7 (15.2)/28 (60.9) 17 (77.3)/5 (22.7) 3 (33.3)/6 (66.7) 0/8 (88.9) 27 (31.4)/47 (54.7) Anti-PD-L1 0/11(23.91) 0/0 0/0 0/1(11.11) 0/12 (14.0) Duration of treatment, median (IQR) 2.7 (1.4–12.2) (0.0–33.4) 9.7 (3.5–11.5) (1.0–30.1) 15.2 (2.7–28.0) (0.5–39.3) 3.9 (2.8–24.2) (0.0–41.0) 4.9 (1.5–16.4) (0.0–41.0) (min-max), months Anti-PD-1 2.4 (1.4–12.6) (0.0–33.4) 9.7 (3.5–11.5) (1.0–30.1) 15.2 (2.7–28.0) (0.5–39.3) 3.6 (2.6–22.1) (0.0–41.0) 4.9 (1.9–17.0) (0–41) Anti-PD-L1 4.2 (1.0–8.2) (0.7–18.9) - - 31.3 (31.3–31.3) (31.3–31.3) 5.9 (1.2–12.3) (0.7–31.3) Reasons to stop the treatment, n (%)* 45 (97.8) 21 (95.5) 7 (77.8) 7 (77.8) 80 (93.0) PD/death 36 (80.0) 8 (38.1) 6 (85.7) 6 (85.7) 56 (70.0) ADR 6 (13.3) 4 (19.1) 1 (14.3) 0 11 (13.8) NED/PR 3 (6.7) 6 (28.6) 0 0 9 (11.3) Other reasons** 0 3 (14.3) 0 1 (14.3) 4 (5.0) Still on treatment at the end of the 1 (2.2) 1 (4.6) 2 (22.2) 2 (22.2) 6 (7.0) study, n (%) Charlson Comorbidity Index Score (0–36). *PD, Progression disease or death related to cancer; NED, no evidence of disease; PR, partial response; ADR, adverse drug reaction. ADR was the only cause of withdrawal in 6 patients. **Other reasons: appendicitis (1), ictus (1), patient withdraw consent (1), cognitive impairment identified at the second visit (1). NSCLC, Non-small cell lung cancer. results of blood tests, diagnostic imaging, or pathological in the European and Spanish regulations (11, 12). Literature anatomy assessments) were periodically reviewed. All patients data corresponding to immune-related adverse drug reactions were followed until 1 month after the end of treatment, (irADRs) were used to classify the ADRs as irADRs (8, 13, 14). irrespective of the reason for discontinuing treatment (e.g., For each adverse effect, the onset date, severity, whether disease progression, adverse effects, death, or other). However, any additional treatment was required, and the outcome were some adverse effects were followed up until the end of the registered. We used the Common Terminology of Clinical study to obtain further information regarding the treatment Adverse Events version 5.0 (CTCAE v5.0) of the Cancer outcome. A total of 86 patients were included, thereby allowing National Institute categorisation to identify grades 3–5 as serious us to estimate the ADR occurrence proportion with a precision and grades 1–2 for all other reactions (15). In addition, the of ±10%. severity of each adverse effect was classified according to the European Union criteria (16). The MedDRA dictionary of medical terminology was used to classify the ADRs, while Outcome measures the drugs used for treatment were classified according to the Anatomical Chemical Classification (ATC) system (17, 18). Information regarding the demographic and clinical The imputability analysis of the drugs and the evaluation variables was collected from the clinical medical records, as of any causal relationship between the drugs and the suspected were variables related to the cancer (i.e., cancer type, date of adverse reactions were analysed using the methods and diagnosis, stage of cancer upon commencing immunotherapy algorithm provided by the Spanish Pharmacovigilance System treatment, and number of previous treatment lines). Complete (SEFV) (19). information related to the immunotherapy treatment employed and regarding other concomitant treatments was also gathered (i.e., type of drug, dosage, and the start/end treatment dates). Data analysis The primary outcome of our study was the characterisation of the ADRs experienced by cancer patients following the The frequencies and incidences of all ADRs and irADRs initiation of immune checkpoint therapy. The definition of were calculated during the study period. In addition, the ADRs used for the purpose of this study was as that stated ADR frequency was analysed by taking into account the Frontiers in Medicine 04 frontiersin.org Sabaté Gallego et al. 10.3389/fmed.2022.891179 TABLE 2 Adverse drug reactions by system organ class disorders. System organ class irADRs Patients* non irADRs Patients* All ADRs Patients* n (%) n (%) n (%) n (%) n (%) n (%) Skin and subcutaneous tissue 50 (32.1) 34 (54.0) 2 (1.0) 2 (3.0) 52 (14.7) 36 (48.0) Alopecia 1 1 0 0 1 1 Dermatitis psoriasiform 1 1 0 0 1 1 Dry skin 10 10 0 0 10 10 Eczema 1 1 0 0 1 1 Erythema 4 4 0 0 4 4 Exfoliative rash 1 1 0 0 1 1 Hyperhidrosis 0 0 1 1 1 1 Hyperkeratosis 1 1 0 0 1 1 Nail discolouration 1 1 0 0 1 1 Nail growth abnormal 1 1 0 0 1 1 Penile ulceration 1 1 0 0 1 1 Plantar erythema 1 1 0 0 1 1 Pruritus 16 16 0 0 16 16 Rash 5 5 0 0 5 5 Rash pruritic 2 2 0 0 2 2 Seborrhoeic dermatitis 1 1 0 1 1 2 Skin exfoliation 2 2 0 0 2 2 Vitiligo 1 1 0 0 1 1 General and administration site cond. 3 (1.9) 3 (4.8) 46 (23.4) 35 (53.0) 49 (13.9) 36 (48.0) Asthenia 0 0 13 13 13 13 Fatigue 0 0 16 16 16 16 Feeling cold 0 0 3 3 3 3 Gait disturbance 0 0 1 1 1 1 Malaise 0 0 1 1 1 1 Mucosal dryness 3 3 0 0 3 3 Oedema peripheral 0 0 4 4 4 4 Pyrexia 0 0 7 7 7 7 Thirst 0 0 1 1 1 1 Gastrointestinal 29 (18.6) 21 (33.3) 18 (9.1) 15 (22.7) 47 (13.3) 33 (44.0) Abdominal pain 0 0 2 2 2 2 Autoimmune colitis 1 1 0 0 1 1 Constipation 0 0 6 6 6 6 Dental dysaesthesia 0 0 1 1 1 1 Diarrhoea 13 12 0 0 13 12 Dry mouth 10 10 0 0 10 10 Lip oedema 0 0 2 1 2 1 Nausea 0 0 6 6 6 6 Stomatitis 5 5 0 0 5 5 Vomiting 0 0 1 1 1 1 Infections and infestations 1 (0.6) 1 (1.06) 39 (19.8) 25 (37.9) 40 (11.3) 25 (33.3) Bronchitis 0 0 4 3 4 3 Campylobacter gastroenteritis 0 0 1 1 1 1 Conjunctivitis 0 0 2 2 2 2 Conjunctivitis viral 0 0 1 1 1 1 Cytomegalovirus gastrointestinal infection 0 0 1 1 1 1 (Continued) Frontiers in Medicine 05 frontiersin.org Sabaté Gallego et al. 10.3389/fmed.2022.891179 TABLE 2 Continued System organ class irADRs Patients* non irADRs Patients* All ADRs Patients* n (%) n (%) n (%) n (%) n (%) n (%) Herpes zoster 0 0 1 1 1 1 Hordeolum 0 0 2 1 2 1 Influenza 0 0 1 1 1 1 Lower respiratory tract infection 0 0 1 1 1 1 Lower respiratory tract infection bacterial 0 0 1 1 1 1 Onychomycosis 0 0 1 1 1 1 Oral herpes 0 0 1 1 1 1 Oral infection 0 0 1 1 1 1 Other 0 0 1 1 1 1 Otitis externa 0 0 1 1 1 1 Peritonsillar abscess 0 0 1 1 1 1 Pneumonia 0 0 2 2 2 2 Respiratory tract infection 0 0 5 5 5 5 Rhinitis 1 1 0 0 1 1 Staphylococcal skin infection 0 0 1 1 1 1 Tooth abscess 0 0 1 1 1 1 Upper respiratory tract infection 0 0 4 3 4 3 Urinary tract infection 0 0 4 4 4 4 Urosepsis 0 0 1 1 1 1 Metabolism and nutrition 3 (1.9) 3 (4.8) 25 (12.7) 24 (36.4) 28 (7.9) 25 (33.3) Abnormal loss of weight 0 0 2 2 2 2 Decreased appetite 0 0 14 14 14 14 Diabetic ketoacidosis 1 1 0 0 1 1 Hyperamylasaemia 2 2 0 0 2 2 Hypercholesterolaemia 0 0 3 3 3 3 Hyperkalaemia 0 0 2 2 2 2 Hypomagnesaemia 0 0 1 1 1 1 Hyponatraemia 0 0 1 1 1 1 Polydipsia 0 0 2 2 2 2 Musculoskeletal and connective tissue 17 (10.9) 16 (25.4) 5 (2.5) 5 (7.6) 22 (6.2) 18 (24.0) Arthralgia 8 7 0 0 8 7 Bursitis 0 0 1 1 1 1 Muscle rigidity 0 0 1 1 1 1 Muscle spasms 0 0 2 2 2 2 Musculoskeletal pain 3 3 0 0 3 3 Myalgia 4 4 0 0 4 4 Osteonecrosis 0 0 1 1 1 1 Polyarthritis 1 1 0 0 1 1 Tendon pain 1 1 0 0 1 1 Respiratory, thoracic and mediastinal 10 (6.4) 8 (12.7) 12 (6.1) 11 (16.7) 22 (6.2) 17 (22.7) Acute interstitial pneumonitis 1 1 0 0 1 1 Cough 0 0 5 5 5 5 Increased viscosity of upper respiratory 0 0 1 1 1 1 secretion Lung infiltration 1 1 0 0 1 1 Organising pneumonia 1 1 0 0 1 1 Pneumonitis 1 1 0 0 1 1 (Continued) Frontiers in Medicine 06 frontiersin.org Sabaté Gallego et al. 10.3389/fmed.2022.891179 TABLE 2 Continued System organ class irADRs Patients* non irADRs Patients* All ADRs Patients* n (%) n (%) n (%) n (%) n (%) n (%) Productive cough 0 0 3 3 3 3 Pulmonary embolism 0 0 1 1 1 1 Respiratory failure 0 0 1 1 1 1 Rhinorrhoea 4 4 0 0 4 4 Suffocation feeling 0 0 1 1 1 1 Throat irritation 2 2 0 0 2 2 Nervous system 0 0 19 (9.6) 17 (25.8) 19 (5.4) 17 (22.7) Balance disorder 0 0 1 1 1 1 Dizziness 0 0 1 1 1 1 Dysgeusia 0 0 3 3 3 3 Headache 0 0 3 3 3 3 Paraesthesia 0 0 9 9 9 9 Tonic clonic movements 0 0 1 1 1 1 Tremor 0 0 1 1 1 1 Endocrine 14 (9.0) 13 (20.6) 0 0 14 (4.0) 13 (17.3) Adrenal insufficiency 6 6 0 0 6 6 Hypophysitis 1 1 0 0 1 1 Hypopituitarism 1 1 0 0 1 1 Hypothyroidism 6 6 0 0 6 6 Eye 12 (7.7) 8 (12.7) 2 (1.0) 2 (3.0) 14 (4.0) 10 (13.3) Conjuctival hyperaemia 1 1 0 0 1 1 Corneal disorder 1 1 0 0 1 1 Corneal erosion 1 1 0 0 1 1 Dry eye 3 3 0 0 3 3 Eye pruritus 2 2 0 0 2 2 Eyelid cyst 1 1 0 0 1 1 Photophobia 1 1 0 0 1 1 Presbyopia 0 0 1 1 1 1 Vision blurred 2 2 0 0 2 2 Vitreous floaters 0 0 1 1 1 1 Blood and lymphatic system 3 (1.9) 3 (4.8) 11 (5.6) 7 (10.6) 14 (4.0) 10 (13.3) Anaemia 0 0 6 6 6 6 Eosinophilia 2 2 0 0 2 2 Leukocytosis 0 0 1 1 1 1 Lymphopenia 0 0 2 2 2 2 Neutrophilia 0 0 1 1 1 1 Thrombocytopenia 1 1 0 0 1 1 Thrombocytosis 0 0 1 1 1 1 Hepatobiliary 12 (7.7) 10 (15.9) 0 0 12 (3.4) 10 (13.3) Cholestasis 3 3 0 0 3 3 Cholestatic liver injury 6 6 0 0 6 6 Hepatocellular injury 3 2 0 0 3 2 Renal and urinary 2 (1.3) 2 (3.2) 6 (3.0) 6 (9.1) 8 (2.3) 8 (10.7) Other 0 0 3 3 3 3 Renal failure 0 0 2 2 2 2 Renal impairment 1 1 0 0 1 1 (Continued) Frontiers in Medicine 07 frontiersin.org Sabaté Gallego et al. 10.3389/fmed.2022.891179 TABLE 2 Continued System organ class irADRs Patients* non irADRs Patients* All ADRs Patients* n (%) n (%) n (%) n (%) n (%) n (%) Tubulointerstitial nephritis 1 1 0 0 1 1 Urinary incontinence 0 0 1 1 1 1 Psychiatric 0 0 6 (3.0) 6 (9.1) 6 (1.7) 6 (8.0) Apathy 0 0 2 2 2 2 Depression 0 0 1 1 1 1 Depressive symptom 0 0 1 1 1 1 Other 0 0 1 1 1 1 Terminal insomnia 0 0 1 1 1 1 Vascular 0 0 5 (2.5) 5 (7.6) 5 (1.4) 5 (6.7) Hypertension 0 0 3 3 3 3 Hypotension 0 0 1 1 1 1 Thrombophlebitis 0 0 1 1 1 1 a Neoplasms benign, malignant and NOS 0 0 1 (0.5) 1 (1.5) 1 (0.3) 1 (1.3) Basal cell carcinoma 0 0 1 1 1 1 Total 156 (100) 63 (100) 197 (100) 66 (100) 353 (100) 75 (100) *Patients may have more than one ADR. a NOS, not otherwise specified; ADR, adverse drug reactions; irADR, immunorelated adverse drug reaction. following criteria: the affected organ/system, the reaction comorbidity index was 4 (IQR: 2–6). The most frequent cancer seriousness, whether the reaction was immune-related or late- was non-small cellular lung cancer (46 cases, 53.5%), followed onset immune-related, and the drug treatment employed. by melanoma (22 cases, 25.6%). Twenty-seven patients (31.4%) The ADR outcomes were described along with the type received a first line treatment (Figure 1, Table 1). Fourteen of treatment and the reason for discontinuing treatment. For patients (16%) suffered from a locally advanced disease, and 72 analysis of the ADR management protocol, four categories were (84%) exhibited metastasis. considered: non-intervention or hygienic-dietetic measures, A total of 74 patients (86%) were treated with anti-PD-1 surgery, transfusion, and pharmacological measures. drugs and 12 (14%) were treated with anti-PD-L1 drugs. The The reaction frequencies and proportions were used median treatment durations were 4.9 (IQR: 1.9–17.0) and 5.9 for the descriptive analysis of the categorical variables, months (IQR: 1.2–12.3), respectively (Table 1). while the median, the Q1 and Q3 quartile values, Treatment was stopped in 80 patients for the following and the minimum/maximum values were used for the reasons: i) 56 patients (70%), disease progression or death; ii) 11 continuous variables. patients (14%), the occurrence of an ADR; iii) 9 patients (11%), The ADR incidences were calculated by dividing the no evidence of disease (complete response) or a partial response; number of ADRs by the corresponding time in treatment and and iv) 4 patients (5%), other reasons. A total of 6 patients were were expressed in cases per 100 patients per year (p-y) of still under treatment at the end of the study (median 31 months, exposure; the 95% confidence intervals were estimated from the IQR 27.9–33.4) (Figure 1, Table 1). Poisson distribution. R The analyses were performed using SAS 9.4 software (SAS Institute Inc., Cary, NC, United States). Adverse drug reactions: Overall and immune-related reactions Results During the follow-up, 75 patients (87.2%) were found to General patient characteristics have reported a total of 353 ADRs, representing a global incidence of 215.5 ADRs/100 p-y following treatment (CI 95%: Out of the 99 patients identified, 86 met the inclusion 194.2–239.2). Skin reactions (52 cases, 15%), general disorders criteria. The total cohort follow up was a median of 5.68 (49 cases, 14%) (such as asthenia, fatigue andpyrexia), and months (IQR: 2.8–20). The majority were male (67.4%), with a gastrointestinal disorders (47 cases, 13%) were the most frequent median age of 66 years (IQR: 59–76), and the median Charlson (Table 2). Frontiers in Medicine 08 frontiersin.org Sabaté Gallego et al. 10.3389/fmed.2022.891179 FIGURE 2 Frequency of adverse drug reactions by system organ class disorders. *NOS, not otherwise specified; irADR, immune-related adverse drug reaction. In 63 patients (73%), a total of 156 (44% of the total number and 2 affected the renal and urinary system (100% of the renal of ADR) irADRs were recorded, representing an incidence of and urinary system irADRs) (Figure 3, Supplementary Table S2). 95.3 irADRs/100 p-y (CI 95%: 81.4–111.4). More specifically, The detailed reactions, and all their characteristics are described skin disorders (50 cases, 32% of the 156 irADRs) with an in Table 3. incidence of 30.5 irADRs/100 p-y (23.1–40.3), gastrointestinal Regarding the seriousness of the reactions, 37 ADRs disorders (29 cases, 19%) with an incidence of 17.7 irADRs/100 (10.5%) were categorized as grades 3–4, and 3 (1%) were p-y (12.3–25.5), musculoskeletal disorders (17 cases, 11%) categorized as grade 5 (death). Twelve of the irADRs (7.7%) with an incidence of 10.4 irADRs/100 p-y (6.5–16.70), and were categorized as grades 3–4, and of these, 4 were diarrhoea, 3 endocrine disorders (14 cases, 9%) with an incidence of 8.6 were hepatocellular injuries, and the remainder consisted of one irADRs/100 p-y (5.1–14.4) were the most frequent (Figure 2, each of the following: diabetic ketoacidosis, hyperamylasaemia, Supplementary Table S1). polyarthritis, acute interstitial and tubulointerstitial nephritis, Of the overall ADRs, in 45 cases (12% of the total number and pneumonitis. Only 2 irADRs (1.3%) were categorized of ADRs) the latency period was ≥12 months, while a total of as grade 5 (autoimmune colitis and hypopituitarism), the 22 irADRs (14% of the total number of irADRs) had a latency autoimmune colitis had a late presentation (>12 months) period of ≥12 months. Of these, 8 irADRs (27.6% of total (Tables 3, 4, Supplementary Table S1). gastrointestinal irADRs) affected the gastrointestinal system, 4 In terms of ADR management, pharmacological treatment affected the eyes (33.3% of total eye irADRs), 4 affected skin and was required for 147 ADRs (41.7%) in 58 patients (77.3%), subcutaneous tissue (8% of total skin and subcutaneous irADRs) while 199 ADRs (56.5%) in 68 patients required no intervention Frontiers in Medicine 09 frontiersin.org Sabaté Gallego et al. 10.3389/fmed.2022.891179 FIGURE 3 Latency period of immune-related adverse reactions. or only hygienic-dietetic measures. In addition, 61 irADRs specialities who manage the rare, but clinically important, (39.1%) in 36 patients required pharmacological treatmen and, organ-specific irADRs. of these, 47 irADRs (30.1%) in 21 patients required treatment In our study, the percentage of patients suffering from with corticosteroids, including oral and topical treatments. In irADRs was found to be similar to that described by Nigro only one case did the irADR require treatment with infliximab et al. in their retrospective study (76%), but higher than that (Table 5, Supplementary Table S3). Additionally, in 13 patients reported by Majzoub et al. who quoted a figure of only 25% treated with corticosteroids, it was necessary to interrupt the (9, 10). The criteria used for categorisation of the ADRs as immunotherapy treatment; this interruption was permanent for immune-related based on the organ/system involved or through 7 patients and temporary for the remainder. the literature identification, could explain these differences. In In terms of the ADR outcome, in 272 of the total ADRs addition, intensive monitoring methods (monthly contact by (77.1%), a “recovered” outcome was recorded, as was also the telephone and structured interviews) were used in our study case for 111 (71.2%) of the irADRs. There were a total of 46 to identify patients suffering from irADRs, and such frequent ADRs (13%) and 23 irADRs (14.7%) with a “non-recovered” contact could also account for the identification of greater outcome (Table 4). numbers of affected patients. Regarding the severity of the irADRs, a similar percentage of irADRs was categorized as grade 3 or above in our study compared to that reported by Nigro et al. (i.e., 9.6%) (9). However, based on a meta-analysis involving Discussion 125 clinical trials, Y. Wang et al. reported that 14% of irADRs were grade 3 or above (20). These differences could be explained In the present study we characterised the occurrence of by considering the means by which the adverse reactions were ADRs, specifically irADRs, in cancer patients treated with selected, since in the above meta-analysis, all adverse events were immunotherapy in real-world clinical practice. The majority gathered, whereas in our study, only the adverse drug reactions of patients experienced adverse reactions (87.2%), although were evaluated. most reactions were mild, with only 11.5% being categorized as Of the various irADRs described in the present study, the grade 3 or above. A high percentage of the ADRs (44%) were most frequent reactions were those affecting the skin, followed immune-related, with skin disorders, gastrointestinal disorders, by general disorders, and those affecting the gastrointestinal musculoskeletal disorders, and endocrine reactions being the system. These results are consistent with those described in the most frequent. It is important to describe these results as they two retrospective studies and in both meta-analyses by Y. Wang may have major implications for clinicians across multiple et al. and P.F. Wang et al., wherein diarrhoea, colitis, and skin Frontiers in Medicine 10 frontiersin.org Sabaté Gallego et al. 10.3389/fmed.2022.891179 TABLE 3 Characteristics of late immune-related ADRs. Severity Management Endocrine Hypothyroidism G1 Chronic treatment with Levothyroxine. Immunotherapy was continued. Eye Conjunctival hyperaemia G2 No treatment required. Immunotherapy withdrawn for another reason. Recovered Corneal disorder G1 Eye lubricating drops. Immunotherapy was continued. Recovered Corneal erosion G1 Ocular antibiotic treatment. Immunotherapy was continued. Recovered Eyelid cyst G2 Surgery. Immunotherapy was continued. Recovered Gastrointestinal Autoimmune colitis G5 Prednisone and infliximab treatment. Immunotherapy withdrawal. Death Diarrhoea G3 Serum therapy and antidiarrheal treatment. Immunotherapy was delayed for a week. Recovered Diarrhoea G3 Antidiarrheal treatment. Immunotherapy was continued. Recovered Diarrhoea G3 Serum and antidiarrheal treatment. Immunotherapy withdrawal for PD. Recovered Diarrhoea G2 Hygienic-dietetic measures. Immunotherapy was continued. Recovered Diarrhoea G2 Treatment with prednisone. Immunotherapy completed. Not recovered. Diarrhoea G1 Antidiarrheal treatment. Immunotherapy delayed for a week. Recovered Stomatitis G2 Nystatin treatment. Immunotherapy was continued. Recovered Musculoskeletal and connective tissue Arthralgia G1 No treatment required. Immunotherapy stopped for another reason. Recovered. Renal and urinary Renal impairment G1 Serum therapy. Immunotherapy continued. Recovered Tubulointerstitial nephritis G3 Prednisone treatment. Immunotherapy withdrawal for PD. Recovered Respiratory, thoracic and mediastinal Lung infiltration G2 No treatment required. Immunotherapy withdrawal. Recovered. Pneumonitis G1 No treatment required. Immunotherapy delayed for a week. Recovered. Skin and subcutaneous tissue Dermatitis psoriasiform G2 Prednisone and topical antiinfective treatment. Immunotherapy withdrawal for symptoms persistence. Recovered Dry skin G1 Hygienic-dietetic measures. Immunotherapy continued. Recovered Pruritus G1 Hygienic-dietetic measures. Immunotherapy continued. Recovered Pruritus G1 No treatment required. Immunotherapy withdrawal for another adverse drug reaction (worsening of renal impairment). Recovered disorders were among the most frequently reported reactions was not described in that published by Baxi et al. (4, 19). In (9, 10, 19, 21). our study, the information related to the diagnosis of adrenal Importantly, it should be mentioned that although insufficiency was collected from the medical records of patients; endocrinopathies associated with immunotherapy are not the however, we cannot rule out the possibility that some of these most common irADRs reported in clinical trials, if they fail to cases were secondary to hypophysitis. Based on the above be quickly and accurately recognised, they have the potential to analyses, it is therefore apparent that intensive surveillance is become life-threatening. In this context, we note that a relatively necessary to diagnose these irADRs, and this is of particular high percentage and incidence of endocrine-related irADRs importance since these cases may present with non-specific (i.e., 9%) were reported in our study, while in the meta-analysis symptoms (8). by P.F. Wang et al., endocrine irADRs were reported for <2% In terms of pneumonitis, we found a frequency of 3% when of treated patients (20). Surprisingly, our data show that adrenal all presentations were included (i.e., interstitial pneumonitis, insufficiency and, hypothyroidism, were the most frequent lung infiltration, and organised pneumonia). This proportion is endocrine-related irADR, with an incidence of 3.66 ADRs/100 similar to those reported in previous studies, such as in the meta- p-y each. The occurrence of adrenal insufficiency was lower analysis by Y. Wang et al. (i.e., 2.8%) (19). However, we note in the published meta-analysis by Y. Wang et al. (0.7%), and that in a retrospective study by Majzoub et al., the percentage Frontiers in Medicine 11 frontiersin.org Sabaté Gallego et al. 10.3389/fmed.2022.891179 TABLE 4 Adverse drug reactions, severity, and outcome. Adverse drug reactions All ADRs All irADRs Early-irADRs Late-irADRs n (%) 353 (100) 156 (44.47) 134 (100) 22 (100) ICI treatment Anti-PD-1 301 (85.3) 134 (85.9) 114 (85.1) 20 (90.9) Anti-PD-L1 52 (14.7) 22 (14.1) 20 (14.9) 2 (9.1) Severity of ADRs G1–G2 313 (88.7) 142 (91.0) 125 (93.3) 17 (77.3) G3–G4 37 (10.5) 12 (7.7) 8 (5.9) 4 (18.2) G5 3 (0.9) 2 (1.3) 1 (0.8) 1 (4.5) Outcome Recovered 272 (77.1) 111 (71.2) 92 (82.9) 19 (17.1) Recovering 27 (7.7) 19 (12.2) 17 (89.5) 2 (10.5) Not recovered 46 (13.0) 23 (14.7) 23 (100) 0 Death 3 (0.9) 2 (1.3) 1 (50.0) 1 (50.0) Unknown 5 (1.4) 1 (0.6) 1 (100) 0 ADRs, Adverse drug reactions; irADRs, immune-related ADRs; early-irADRs, immune-related ADRs with a latency period less than 12 months; late-irADRs, immune-related ADRs with a latency period equal or greater than 12 months. varied from 7.1% with nivolumab to 3.2% with ipilimumab (10). required corticosteroid treatment, while 15.2 and 22% required Despite its relatively low instance, pneumonitis is potentially their treatment to be interrupted (9). In our study, other life-threatening, and so surveillance is also necessary for this pharmacological interventions for the treatment of diarrhoea, particular irADR. It should be noted here that for the purpose arthralgia, and other minor ADRs were also recorded, thereby of our study, we did not include patients who had received resulting in higher percentages of patients receiving treatment. combinations with ipilimumab. The main strength of the present study is that it was specially Regarding the latency period, which is considered to be one designed to evaluate ADRs, and in particular, irADRs. The of the areas of uncertainty, our data suggested that 14% of the prospective nature of this study and the intensive monitoring irADRs appeared after 12 months from the start of treatment. of ADRs, along with the review of medical records and However, Nigro et al. found that 30% of patients presented monthly phone calls to patients, allowed the comprehensive with a late-onset irADR. These differences may be due to the detection of ADRs. Moreover, the specific definition of an inclusion criteria employed in each study, since in the study by adverse reaction (11, 12) allowed us to rule out other concurrent Nigro et al., only patients with a minimum treatment duration events that were reported in previous studies. Furthermore, of 12 months were included. In contrast, in a high proportion we systematically evaluated the causal relationships between of patients included in our study (65%), it was necessary to the treatments employed and the suspected adverse reactions interrupt immunotherapy due to disease progression, thereby using the methods and algorithm provided by the Spanish resulting in a shorter follow-up period for these patients. In both Pharmacovigilance System (SEFV) (18). In addition, the long- our study and in that by Nigro et al., it was found that a higher term follow-up period and the specific attention paid to a variety frequency of irADRs occurred in the early latency period rather of irADRs are expected to enhance our understanding of ADRs. than in the late one (9). However, it should also be noted that some limitations can We also found that a high proportion of patients required be found in our study. Firstly, it was a unicentric study, and some kind of pharmacological measure to treat their ADRs. In the number of patients included was not sufficient to provide some cases, this was a permanent therapy replacement, as in specific information related to each evaluated drug. However, the case of the endocrine irADRs. Such measures increase the a high percentage of the total cancer patients from throughout complexity of patient management, in addition to resulting in a Catalunya attend our hospital. In addition, as the use of temporary or permanent interruption of their immunotherapy immunotherapy is increasing and the characteristics of treated treatment. Furthermore, the need to administer corticosteroids patients may vary over time, the generalisability of our study in 21 (24%) patients and the necessity to interrupt treatment could be affected. Furthermore, we did not evaluate combination in 13 (15%) patients constitute lower numbers than those therapies since the objective of this study was to monitor a reported by Nigro et al., where 51 and 56% of patients suffering unique active ingredient so as to avoid the contribution of other from early-onset irADRs and late-onset irADRs, respectively, drugs when considering the attribution of causation. Finally, Frontiers in Medicine 12 frontiersin.org Sabaté Gallego et al. 10.3389/fmed.2022.891179 TABLE 5 Management of adverse drug reactions. n (%) All ADRs* Patients irADRs Patients 353 (100) 75 (100) 156 (100) 63 (100) No intervention or hygienic-dietetic measures 199 (56.5) 68 (90.7) 94 (60.3) 50 (79.4) Surgery treatment 3 (0.9) 3 (4.0) 1 (0.6) 1 (1.6) Transfusion 3 (0.9) 3 (4.0) 0 (0) 0 Pharmacological measures**, n (%) 147 (41.7) 58 (77.3) 61 (39.1) 36 (57.1) Analgesics 19 11 8 6 Antibacterials for systemic use 45 28 9 6 Antidiarrheals, intestinal antiinflammatory/antiinfective 15 10 15 10 Agents acting on the renin-angiotensin system 7 3 0 0 Antihistamines for systemic use 10 8 9 7 Antiinflammatory and antirheumatic products 7 5 5 3 Corticosteroids, dermatological preparations 11 7 10 6 Corticosteroids for systemic use 51 20 37 16 Diuretics 7 6 0 0 Drugs for obstructive airway diseases 6 3 0 0 Drugs for functional gastrointestinal disorders 9 8 1 1 Drugs for acid related disorders 5 4 0 0 Ophthalmologicals 12 5 3 2 Nasal preparations 5 4 3 2 Cough and cold preparations 5 5 0 0 Topical products for joint and muscular pain 5 3 4 3 Thyroid therapy 14 6 14 6 Others*** 54 21 22 9 *Management was unknown in one ADR. **Patients can be treated with one or more pharmacological measures; in 3 ADRs (1 patient) information on the specific drug was not available. ***See details of other therapeutic groups with a frequency less than 5 on Supplementary Table S2. as mentioned above, we note that in a high proportion of be life-threatening. It is also possible that such irADRs could patients, it was necessary to interrupt treatment due to disease affect the continuation of immunotherapy treatment. progression, ultimately resulting in a short follow-up period for those patients. Data availability statement The raw data supporting the conclusions of this article will Conclusion be made available by the authors, without undue reservation. In our prospective observational study carried out at Ethics statement the Vall d’Hebron University Hospital (Catalunya, Spain), the majority of cancer patients treated with immunotherapy The studies involving human participants were reviewed and (i.e., monotherapy of PD1/PDL1 (programmed death-ligand approved by Vall d’Hebron Hospital Ethical Committee. The 1) checkpoint inhibitors) experienced adverse drug reactions patients/participants provided their written informed consent to (ADRs). Although most reactions were mild, 11.5% were participate in this study. categorised as grade 3 or above. In addition, a high percentage of the ADRs were immune-related ADRs (irADRs) that occurred at any time during treatment, and therefore the early identification Author contributions of such reactions through the close monitoring of patients is recommended. Indeed, the real-world data reported herein MS, NG, M-JC, AF, EF, IB, JC, RM, and EM-C participated emphasise the requirement for the strict monitoring and in the conception and design, interpretation of data, and writing multidisciplinary management of irADRs due to the fact that the paper. EP participated in the conception and design, data they often require pharmacological interventions, or could even analysis, interpretation of data, and writing the paper. XV Frontiers in Medicine 13 frontiersin.org Sabaté Gallego et al. 10.3389/fmed.2022.891179 participated in the design and data analysis. AA participated The reviewer FMV declared a shared affiliation, with in the conception and design, interpretation of data, writing several of the authors MS, XV, and AA at the time of the paper, and coordinated the whole project. All authors the review. contributed to the review and approved the final version of the manuscript. Publisher’s note Acknowledgments All claims expressed in this article are solely those of the authors and do not necessarily represent those We thank all the patients who consented to participate in of their affiliated organizations, or those of the publisher, this study, in addition to the oncology day hospital nursing the editors and the reviewers. Any product that may be team of the Vall d’Hebron University Hospital for their evaluated in this article, or claim that may be made by collaboration and help in developing the project. We would also its manufacturer, is not guaranteed or endorsed by the like to thank Angus Powles and Laura Boyd for the English publisher. language corrections. Conflict of interest Supplementary material The authors declare that the research was conducted in the The Supplementary Material for this article can be absence of any commercial or financial relationships that could found online at: https://www.frontiersin.org/articles/10.3389/ be construed as a potential conflict of interest. fmed.2022.891179/full#supplementary-material References 1. EMA. Opdivo (2022). Available online at: https://www.ema.europa.eu/en/ Unión Europea. L 316/38. Available online at: https://www.boe.es/doue/2012/316/ medicines/human/EPAR/opdivo (accessed January 19, 2022). L00038-00040.pdf (accessed November 14, 2012). 2. EMA. Keytruda (2022). Available online at: https://www.ema.europa.eu/en/ 12. 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