- Email: [email protected]
Safety of nivolumab in metastatic renal cell carcinoma patients: A real-life experience in a Spanish urology setting
Actas Urol Esp. 2019;43(7):364---370
Actas Urol´ ogicas Espa˜ nolas www.elsevier.es/actasuro
ORIGINAL ARTICLE
Safety of nivolumab in metastatic renal cell carcinoma patients: A real-life experience in a Spanish urology setting夽 J. Amores Bermúdez a,∗ , I. Osman García b , M. Unda Urzáiz c , P. Jiménez Marrero d , M.J. Ledo Cepero e , R. Llarena f , J. Flores Martín g , J.I. Abad Vivas-Pérez h , M. Rodrigo Aliaga i , A. Juarez Soto a a
Servicio de Urología, Hospital Universitario de Jerez, Jerez, Spain Servicio de Urología, Hospital Virgen del Rocío, Sevilla, Spain c Servicio de Urología, Hospital Universitario Basurto, Bilbao, Spain d Servicio de Urología, Hospital Universitario Dr. Negrín, Las Palmas de Gran Canaria, Spain e Servicio de Urología, Hospital Universitario Puerta del Mar, Cádiz, Spain f Servicio de Urología, Hospital de Cruces, Baracaldo, Spain g Servicio de Urología, Complejo Hospitalario de Jaén, Jaén, Spain h Servicio de Urología, Hospital de Poniente, El Ejido (Almería), Spain i Servicio de Urología, Hospital General Universitario de Castellón, Castellón, Spain b
Received 1 November 2018; accepted 4 March 2019 Available online 27 July 2019
KEYWORDS Metastatic renal cell carcinoma; Nivolumab; Checkpoint inhibitors; Immunotherapy; Safety; Tolerability
Abstract Introduction and objectives: Nivolumab is an immunotherapy agent that has been an approved treatment for previously treated patients with advanced renal cell carcinoma (RCC). Experience in real-life settings, especially regarding immune-related adverse events, is scarce. We present our experience with reference to the safety of nivolumab in patients with metastatic RCC (mRCC) treated in 9 hospitals in Spain. Material and methods: Retrospective, multicenter study of patients with mRCC treated with nivolumab between 2016 and 2018. Data on baseline socio-demographic and clinical characteristics and drug-related adverse events were collected. Results: The mean age of the 26 patients included was 63.7 ± 11.5 years; 96% were ECOG 0---1 and 78% had favorable or intermediate MSKCC risk scores; 73% had the clear cell histological subtype and 30% metastatic disease. Median follow-up was 9 months (range 1---14). All patients experienced an adverse event at different grades, with fatigue, fever and anemia being the most common (27%). Grade 3 adverse events occurred in 23% of patients. Adverse reactions led to treatment suspension in 3 patients (11%).
夽 Please cite this article as: Amores Bermúdez J, Osman García I, Unda Urzáiz M, Jiménez Marrero P, Ledo Cepero MJ, Llarena R, et al. nola en urología en la práctica clínica Seguridad de nivolumab en pacientes con carcinoma de células renales metastásico: experiencia espa˜ real. Actas Urol Esp. 2019;43:364---370. ∗ Corresponding author. E-mail address: [email protected] (J. Amores Bermúdez).
2173-5786/© 2019 AEU. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
Safety of nivolumab in metastatic renal cell carcinoma patients
365
Conclusion: In the real-life clinical setting, nivolumab shows favorable outcomes, similar to those reported by other studies. © 2019 AEU. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
PALABRAS CLAVE Carcinoma de células renales metastásico; Nivolumab; Inhibidores de puntos de control; Inmunoterapia; Seguridad; Tolerabilidad
Seguridad de nivolumab en pacientes con carcinoma de células renales metastásico: experiencia espa˜ nola en urología en la práctica clínica real Resumen Introducción y objetivo: Nivolumab es un agente inmunoterapéutico aprobado para el tratamiento de pacientes con carcinoma de células renales (CCR) avanzado tratados previamente. La experiencia en práctica clínica real, especialmente en lo referente a la aparición de reacciones adversas inmunorrelacionadas, es escasa. Presentamos la experiencia acerca de la seguridad de nivolumab en pacientes con CCR metastásico (CCRm) tratados en 9 hospitales de Espa˜ na. Material y métodos: Estudio retrospectivo, multicéntrico en pacientes con CCRm tratados con nivolumab entre 2016 y 2018. Se recogieron datos sociodemográficos y clínicos basales y las reacciones adversas relacionadas con el fármaco. Resultados: Los 26 pacientes incluidos presentaron una edad de 63,7 ± 11,5 a˜ nos. El 96% presentaba ECOG 0-1 y el 78% un riesgo MKSCC favorable/intermedio. El 73% presentaba subtipo histológico de células claras y el 30%, metástasis de inicio. La mediana de seguimiento fue de 9 meses (rango: 1-14). El 100% de los pacientes presentó una reacción adversa de cualquier grado; las más frecuentes fueron la fatiga, la fiebre y la anemia (27%). El 23% presentó una reacción adversa de grado 3. Las reacciones adversas llevaron a la suspensión del tratamiento en 3 pacientes (11%). Conclusión: En la práctica clínica real, nivolumab presenta un perfil de seguridad favorable y manejable, similar al descrito en otros estudios. © 2019 AEU. Publicado por Elsevier Espa˜ na, S.L.U. Todos los derechos reservados.
Introduction Renal cell carcinoma (RCC) is considered an ‘‘immunogenic’’ tumor. It has lacked effective therapeutic options for advanced stages of the disease for a long time. Since their development in 2005, inhibitors of vascular endothelial growth factor and mammalian target of rapamycin (mTOR) have represented a considerable advance in the treatment of metastatic RCC (mRCC). In comparison with the standard therapy which includes interferon-␣, placebo or other antiangiogenic treatment,1 these have only been effective increasing progression-free survival, but not overall survivalfor, except for mTOR temsirolimus. The advanced knowledge of the immune reactions of the host against the tumor has allowed the development of new immunotherapeutic agents, such as antibodies against immune checkpoint inhibitors.2,3 Nivolumab is a human immunoglobulin type G4 (IgG4) monoclonal antibody that binds to the programmed death 1 (PD-1) receptor and blocks its interaction with PD-L1 and PD-L2 ligands, which enhances the responses of T lymphocytes, including antitumor cells.4,5 Nivolumab is indicated for the treatment of various tumors.6 It was approved in 2016 for the treatment of adult patients with advanced RCC who had received previous systemic antiangiogenic treatment6 based on the results of the Checkmate 025 phase III study.7 In this study, nivolumab increased overall survival by
5.4 months compared to everolimus (25.0 vs. 19.6 months), an mTOR inhibitor recommended for the treatment of patients with mRCC who have progressed to treatment with vascular endothelial growth factor.1 The rates of adverse reactions with everolimus in any grade (79%) and grade 3---4 (19%), were lower (88% and 34%, respectively).7 Despite the promising results of this clinical trial, studies in real clinical practice providing data about the effectiveness and safety of nivolumab in non-selected patients would be required. Safety is especially significant regarding immune checkpoint inhibitors, since they are associated with a spectrum of immune-related adverse reactions that affect various organ systems.8---10 Although these are usually transient, they can sometimes be of moderate or severe intensity.11 Most of them can be managed safely if they are recognized, diagnosed and treated properly in the early stages of their onset.8 This is why long-term follow-up and information on these or other adverse reactions are essential to optimize the management of patients treated with nivolumab.11 There is no evidence in our country on the safety of nivolumab in mRCC in real clinical practice and is generally scarce in the literature; especially regarding the occurrence of immune-related adverse reactions.12---15 We present the experience about the safety of nivolumab in a cohort of 26 patients with mRCC treated in 9 Spanish hospitals.
366
Methods Design Retrospective analysis of the data from patients with mRCC treated with nivolumab in 9 Spanish hospitals between 2016 and 2018 (n = 26). The demographic and clinical data were extracted (tumor characteristics and classification, presence of metastasis, functional status and risk factors of the patient and previous antiangiogenic treatments for advanced RCC). The functional status of the patients was classified according to the Eastern Cooperative Oncology Group (ECOG).16 For the establishment of the prognostic risk, the classification of the Memorial Sloan Kettering Cancer Center (MSKCC) was used: favorable, intermediate or poor, according to the presence of 0, 1 or 2, and 3 prognostic factors, respectively.17 The Fuhrman nuclear grading system (grades 1, 2, 3 and 4) was used for tumor classification.18 Adverse reactions were assessed at each follow-up visit. The most frequent ones related to the drug as well as others reported by the patients, were collected. Adverse reactions were classified according to the common terminology criteria for adverse reactions, version 4.0 of the National Cancer Institute (USA).19
Statistical analysis We have performed a descriptive data analysis; the categorical variables are expressed by frequencies and percentages and by the mean and the standard deviation (normal distribution) or the median and range (non-normal distribution) for the continuous variables. The relationship between the presence of grade 3 adverse reactions and the characteristics of the patients could not be statistically analyzed due to the low number of events.
Results Patients The 26 patients treated with nivolumab had a mean age of 63.7 ± 11.5 years (range: 38---79 years). Table 1 shows the demographic and clinical baseline characteristics of the patients. 92.3% of the patients (n = 24) had ECOG 0---1 and 78% had a favorable or intermediate MKSCC risk. The histological subtype clear RCC was the most frequent (73%). 30% (n = 8) of the patients presented metastasis at diagnosis; the most frequent were lung (70%). Fuhrman nuclear grade 2 was the most frequent (43%), followed by grade 3 (31%). 96.2% (n = 25) of the patients underwent nephrectomy, of whom 26.9% underwent cytoreductive surgery and 73.1% radical surgery. 73% of the patients had received only one anti-angiogenic treatment for the previous mRCC. The most widely used 1st line treatment was sunitinib (84.6%). The median number of nivolumab cycles was 15.
J. Amores Bermúdez et al. Table 1 Sociodemographic and clinical characteristics of patients. Variables Age, years, Media (SD) Median (range)
63.7 (11.5) 65.5 (38---79)
Sex, n (%) Men Women
22 (84.6) 4 (15.4)
ECOG PS, n (%) 0 1 >2
15 (57.7) 9 (34.6) 2 (7.7)
Pathological stage n (%) T1a T1b T2a T2b T3a T3b
2 3 3 2 14 2
MKSCC risk group, n (%) Favorable Intermediate Poor
6 (23.1) 15 (57.7) 5 (19.2)
Laterality, n (%) Left Right Bilateral
13 (50.0) 11 (42.3) 2 (7.7)
Location at diagnosis, n (%) Organ-confined Metastatic
18 (69.2) 8 (30.8)
Sites of metastasis, n (%)a Lung Adenopathy Bone Liver Pleural
18 14 8 4 2
Adenopathy location Retroperitoneal Mediastinal Both
(8.0) (11.5) (11.5) (8.0) (53.8) (8.0)
(69.2) (53.8) (30.8) (15.4) (7.7)
6 (42.8) 4 (28.5) 4 (28.5)
Histological subtype, n (%) Clear Papillary Mixed
19 (73.1) 4 (15.4) 3 (11.5)
Fuhrman’s nuclear grade, n (%) 2 3 4 n/a
4 11 8 3
Safety profile
Previous nephrectomy, n (%) Yes No
25 (96.2) 1 (3.8)
The median follow-up was 9 months (range: 1---14 months). Adverse reactions of any grade or grade 3---4 are shown
Number of previous antiangiogenic treatments for advanced RCC, n (%)
(15.4) (42.3) (30.8) (11.5)
Safety of nivolumab in metastatic renal cell carcinoma patients
Discussion
Table 1 (Continued) Variables 1 2 3
19 (73.1) 6 (23.1) 1 (3.8)
1st line treatment, n (%) Sunitinib Pazopanib n/a
22 (84.6) 3 (11.5) 1 (3.8)
2nd line treatment, n (%)b Axitinib Pazopanib Everolimus
3 (42.8) 2 (28.5) 2 (28.5)
RCC: renal cell carcinoma; SD: standard deviation; ECOG PS: Eastern Cooperative Oncology Group performance status; MSKCC: Memorial Sloan Kettering Cancer Center; n/a: not available. The percentages refer to valid population. a Patients could have more than one site of metastasis. b n = 7.
Table 2 Frequency of adverse reactions related to the drug during follow-up (median: 9 months). Adverse reaction, n (%) Any Fatigue Fever Anemia Cough Diarrhea Loss of appetite Skin rash Dry mouth Pruritus Dyspepsia Diplopia Dysphonia Tinnitus Hypertension Nephritis Duodenal ulcer Facial hemiparesis Hypertransaminasemia
367
Any grade 20 7 7 7 5 4 4 2 2 2 2 1 1 1 1 1 1 1 1
(76.9) (26.9) (26.9) (26.9) (19.2) (15.4) (15.4) (7.7) (7.7) (7.7) (7.7) (3.8) (3.8) (3.8) (3.8) (3.8) (3.8) (3.8) (3.8)
Grade 3 7 (26.9) ------1 (3.8) --1 (3.8) --------------1 (3.8) 1 (3.8) 1 (3.8) 1 (3.8) 1 (3.8)
in Table 2. 76.9% of the patients (n = 20) presented an adverse reaction of any grade. The most frequent events were fatigue, fever and anemia (27%, n = 7). Seven grade 3 adverse reactions were reported (rate = 27%); the most frequent were loss of appetite, hypertension, nephritis and duodenal ulcer (4%, n = 1). Patients with grade 3 adverse reactions often had papillary or mixed histological subtypes and intermediate or poor MSKCC (Table 3). There were no patients with grade 4 adverse reaction. 3 (11%) patients dropped-out of treatment due to the onset of adverse reactions. These events were managed by competent urologists, in some cases with the support of the corresponding specialists.
The long-term safety and tolerability profile of the treatments available for mRCC are key aspects in the selection of the most appropriate treatment for each patient. In this sense, real clinical practice data are crucial, since they provide relevant information about safety in unselected patients. Our study shows that the safety profile of nivolumab in real clinical practice is consistent with the data available on this drug, with most adverse reactions of mild to moderate reversible severity, including grade 3. Grade 4 adverse reactions were not reported. The information available on the safety of nivolumab monotherapy in patients with mRCC derives from the studies conducted with this treatment until its approval for this indication.4,5,7 These studies show a consistent safety profile of nivolumab7,20 in the same way as it has been observed in the treatment for melanoma and non-small cell lung cancer, without new toxicities requiring special attention being identified.20 The few studies including information from real-life clinical practice in mRCC confirm the consistency of the safety profile of nivolumab even when treating unselected patients and with different follow-up lengths.12,14,15 Our study includes diverse unselected patients, showing that the safety profile of nivolumab in daily clinical practice is similar to that of patients treated with nivolumab in the Checkmate 025 Phase III study (n = 410)7 and, in general, the result of the grouped data of monotherapy treatment for different tumors in 2578 patients.6 The percentage of patients with any adverse reaction of any type in our study (77%) was practically the same as in the Phase III study (79%), while the rate of grade 3---4 adverse reactions was slightly higher (27% versus to 19% in the phase III study). However, we must highlight that all adverse reactions in our study were grade 3. The most frequent adverse reactions associated to this drug in our series were fatigue, fever and anemia, all with an incidence of 27%, and none of these were grade 3. Fatigue was also the most frequent event in the Checkmate 025 study, with a fairly higher incidence (33%: 3% of grade 3---4). However, the incidence of anemia was lower (8%) and there were no cases of fever, an adverse reaction which had been previously classified as ‘‘frequent’’.6 We must remember that anemia could also be a result to the advanced stage of RCC, rather than constituting an adverse reaction to the treatment. In addition to fatigue, the most frequent adverse reactions in the Checkmate 025 study were nausea and pruritus (both with an incidence of 14%, none of grade 3---4).7 In our series of patients, nausea was not reported, and the incidence of pruritus was also somewhat lower (8%, none of grade 3). It should be noted that the Checkmate 025 study only shows the adverse reactions present in ≥10% of the patients of both treatment arms, which may affect the adverse reactions reported in the group treated with nivolumab. This is probably why adverse reactions classified as ‘‘frequent’’ such as dry mouth or hypertension, present in our series in 2 patients (8%) and one patient (4%), respectively, are not mentioned in this study. Nearly 20% of our patients presented cough, in one case (4%) of grade 3. The incidence of this adverse reaction
368
Table 3
Characteristics of patients with grade 3 adverse reactions.
Grade 3 adverse reaction Age (years) Sex
Location
Nephrectomy
Subtype
ECOG MSKCC
Previous lines 1st line treatment
2nd line treatment
Hypertension, nephritis Cough, duodenal ulcer Facial hemiparesis Hypertransaminasemia Loss of appetite
Organ-confined Organ-confined Organ-confined Organ-confined Organ-confined
Radical Radical Radical Radical Radical
Papillary Mixed Clear Papillary Clear
0 1 0 1 0
1 1 2 2 1
----Everolimus Everolimus ---
59.0 52.0 65.0 72.0 33.0
Male Female Male Female Male
Intermediate Poor Intermediate Intermediate Favorable
n/a Sunitinib Sunitinib Sunitinib Sunitinib
ECOG PS: Eastern Cooperative Oncology Group performance status; MSKCC: Memorial Sloan Kettering Cancer Center; n/a: not available.
J. Amores Bermúdez et al.
Safety of nivolumab in metastatic renal cell carcinoma patients classified as ‘‘very frequent’’6 was 9% in the Checkmate 025 study. Loss of appetite, present in 15% of the patients (in one case [4%] of grade 3), had a similar incidence in the Checkmate 025 study (12%), with 2 cases (1%) of grades 3---4. Strikingly, one of the patients in our series developed a gastroduodenal ulcer, an adverse reaction classified as ‘‘rare’’. The most frequent immune-related adverse reactions (>10%) were cutaneous (27%, with 8% skin rash and 8% pruritus) and diarrhea or colitis (15%), none of them grade 3. The incidence of this type of adverse reactions in the Checkmate 025 study was similar: 24% (14% pruritus and 10% skin rash) and 12%, respectively, with an incidence of grade 3---4 of 1% in both cases. Other potentially immune-related adverse reactions in our series of patients were peripheral neuropathy (diplopia, dysphonia, tinnitus and facial hemiparesis) and nephritis, all of them present in only one patient (4%). Adverse reactions led to treatment withdrawal of patients with similar percentages in both studies (11% vs. 8% in the Checkmate 025 study). Regarding the interpretation of our safety results in real clinical practice with respect to those reported in the Checkmate 025 study, we must consider the sociodemographic and clinical differences among patients, as well as the length of follow-up. In the first case, both populations were roughly similar, except for the ratio of patients with clear cell histological subtype or metastasis, which was lower in our series compared with the Checkmate 025 study (73 vs. 100% and 31 vs. 83%, respectively). The percentage of patients who had received one or two previous treatments was similar (73 vs. 72% and 23 vs. 28%, respectively). Regarding follow-up, the median in our series was 9 months (range: 1---14) compared to the minimum 14 months of patients treated with nivolumab in the Checkmate 025 study. The studies including different types of tumors had a follow-up of 28 months, which contributed to include events occurring in the longer term. However, the most frequent adverse reactions (≥10%) in these studies were generally the same as those observed in the Checkmate 025 study and ours: fatigue (30%), rash (17%), pruritus (13%), diarrhea (13%) and nausea (12%).6 Two studies in real clinical practice with mRCC patients have confirmed the safety profile reported in the Checkmate 025 study: one of them included 528 patients with a 13-month follow-up period,12 and the other, 389 patients enrolled in the Italian cohort of the EAP (Expanded Access Program), with a follow-up of 7 months.15,21 In addition to the limitations inherent to the retrospective nature of our study, the low number of patients constitutes a relevant limitation, since it enhances the sensitivity of the occurrence of an event (onset of an adverse reaction), which results in higher rates than those observed in studies with larger cohorts of patients (Checkmate 025). On the other hand, the great number of patients in this study (Checkmate 025) provides information on rare adverse reactions that have not been captured in our study. With regards to immune-related adverse reactions, some of them --- which have been widely described, such as colitis, cutaneous or endocrine --- may have been adequately collected. However, in the case of others less known --- which have not been collected in clinical trials but in the daily clinical practice, such as musculoskeletal problems --- may have not been properly reported.22
369
Conclusion Our experience in real clinical practice shows that nivolumab has a favorable and manageable safety profile, similar to the data described in the pivotal study, in studies in other tumors and other studies in real clinical practice.
Conflicts of interest The authors declare that they have no conflicts of interest.
Acknowledgements The authors would like to thank Beatriz Viejo for her support and help in writing and editing this document.
References 1. Escudier B, Porta C, Schmidinger M, Rioux-Leclercq N, Bex A, Khoo V, et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016;27:v58---68. 2. Inman BA, Harrison MR, George DJ. Novel immunotherapeutic strategies in development for renal cell carcinoma. Eur Urol. 2013;63:881---9. 3. Bedke J, Gouttefangeas C, Singh-Jasuja H, Stevanovic S, Behnes CL, Stenzl A. Targeted therapy in renal cell carcinoma: moving from molecular agents to specific immunotherapy. World J Urol. 2014;32:31---8. 4. McDermott DF, Drake CG, Sznol M, Choueiri TK, Powderly JD, Smith DC, et al. Survival, durable response, and longterm safety in patients with previously treated advanced renal cell carcinoma receiving nivolumab. J Clin Oncol. 2015;33: 2013---20. 5. Motzer RJ, Rini BI, McDermott DF, Redman BG, Kuzel TM, Harrison MR, et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol. 2015;33:1430---7. 6. Opdivo (nivolumab). Ficha técnica [consultado el 3 de julio de 2018]. Disponible en: http://www.ema.europa.eu/ docs/es ES/document library/EPAR - Product Information/ human/003985/WC500189765.pdf. 7. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus everolimus in advanced renalcell carcinoma. N Engl J Med. 2015;373:1803---13. 8. Heinzerling L, Goldinger SM. A review of serious adverse effects under treatment with checkpoint inhibitors. Curr Opin Oncol. 2017;29:136---44. 9. Postow MA, Hellmann MD. Adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378:1165. 10. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378:158---68. 11. Ochoa CE, Joseph RW. Nivolumab in renal cell carcinoma: current trends and future perspectives. J Kidney Cancer VHL. 2018;5:15---8. 12. Albiges L, Negrier S, Dalban C, Gravis G, Chevreau C, Ouard S, et al. Safety and efficacy of nivolumab in metastatic renal cell carcinoma (mRCC): results from the NIVOREN GETUG-AFU 26 study. J Clin Oncol. 2018;36, abstr 577. 13. Stukalin I, Wells JC, Graham J, Yuasa T, Beuselinck B, Kollmannsberger CK, et al. Real world outcomes of nivolumab and cabozantinib in metastatic renal cell carcinoma: results from
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J. Amores Bermúdez et al. the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). J Clin Oncol. 2018;36:615. Ratta R, Grassi P, Verzoni E, Mennitto A, de Braud F, Procopio G. Nivolumab in metastatic renal cell carcinoma (mRCC) patients: a real world single-center experience. Ann Oncol. 2016;27:iv29---38. De Giorgi U, Carteni G, Giannarelli D, Basso U, Galli L, Cortesi E, et al. Safety and efficacy of nivolumab for metastatic renal cell carcinoma: real-world results from an expanded access program. BJU Int. 2018. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649---55. Motzer RJ, Bacik J, Schwartz LH, Reuter V, Russo P, Marion S, et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol. 2004;22:454---63. Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol. 1982;6:655---63.
19. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) version 4.0; 2015. Available from: https://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm [accessed 06.07.18]. nola de Oncología Médica. Informe SEOM de eval20. Sociedad Espa˜ ® uación de fármaco: Nivolumab (Opdivo ) para el tratamiento en monoterapia del carcinoma de células renales avanzado tras progresión a tratamiento previo [consultado el 6 de julio de 2018]. Disponible en: https://seom.org/seomcms/ images/stories/Informes SEOM/IPT Nivolumab renal.pdf. 21. Vitale MG, Scagliarini S, Galli L, Pignata S, Lo Re G, Berruti A, et al. Efficacy and safety data in elderly patients with metastatic renal cell carcinoma included in the nivolumab Expanded Access Program (EAP) in Italy. PLOS ONE. 2018;13:e0199642. 22. Baxi S, Yang A, Gennarelli RL, Khan N, Wang Z, Boyce L, et al. Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis. BMJ. 2018;360, k793.
Actas Urol´ ogicas Espa˜ nolas www.elsevier.es/actasuro
ORIGINAL ARTICLE
Safety of nivolumab in metastatic renal cell carcinoma patients: A real-life experience in a Spanish urology setting夽 J. Amores Bermúdez a,∗ , I. Osman García b , M. Unda Urzáiz c , P. Jiménez Marrero d , M.J. Ledo Cepero e , R. Llarena f , J. Flores Martín g , J.I. Abad Vivas-Pérez h , M. Rodrigo Aliaga i , A. Juarez Soto a a
Servicio de Urología, Hospital Universitario de Jerez, Jerez, Spain Servicio de Urología, Hospital Virgen del Rocío, Sevilla, Spain c Servicio de Urología, Hospital Universitario Basurto, Bilbao, Spain d Servicio de Urología, Hospital Universitario Dr. Negrín, Las Palmas de Gran Canaria, Spain e Servicio de Urología, Hospital Universitario Puerta del Mar, Cádiz, Spain f Servicio de Urología, Hospital de Cruces, Baracaldo, Spain g Servicio de Urología, Complejo Hospitalario de Jaén, Jaén, Spain h Servicio de Urología, Hospital de Poniente, El Ejido (Almería), Spain i Servicio de Urología, Hospital General Universitario de Castellón, Castellón, Spain b
Received 1 November 2018; accepted 4 March 2019 Available online 27 July 2019
KEYWORDS Metastatic renal cell carcinoma; Nivolumab; Checkpoint inhibitors; Immunotherapy; Safety; Tolerability
Abstract Introduction and objectives: Nivolumab is an immunotherapy agent that has been an approved treatment for previously treated patients with advanced renal cell carcinoma (RCC). Experience in real-life settings, especially regarding immune-related adverse events, is scarce. We present our experience with reference to the safety of nivolumab in patients with metastatic RCC (mRCC) treated in 9 hospitals in Spain. Material and methods: Retrospective, multicenter study of patients with mRCC treated with nivolumab between 2016 and 2018. Data on baseline socio-demographic and clinical characteristics and drug-related adverse events were collected. Results: The mean age of the 26 patients included was 63.7 ± 11.5 years; 96% were ECOG 0---1 and 78% had favorable or intermediate MSKCC risk scores; 73% had the clear cell histological subtype and 30% metastatic disease. Median follow-up was 9 months (range 1---14). All patients experienced an adverse event at different grades, with fatigue, fever and anemia being the most common (27%). Grade 3 adverse events occurred in 23% of patients. Adverse reactions led to treatment suspension in 3 patients (11%).
夽 Please cite this article as: Amores Bermúdez J, Osman García I, Unda Urzáiz M, Jiménez Marrero P, Ledo Cepero MJ, Llarena R, et al. nola en urología en la práctica clínica Seguridad de nivolumab en pacientes con carcinoma de células renales metastásico: experiencia espa˜ real. Actas Urol Esp. 2019;43:364---370. ∗ Corresponding author. E-mail address: [email protected] (J. Amores Bermúdez).
2173-5786/© 2019 AEU. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
Safety of nivolumab in metastatic renal cell carcinoma patients
365
Conclusion: In the real-life clinical setting, nivolumab shows favorable outcomes, similar to those reported by other studies. © 2019 AEU. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
PALABRAS CLAVE Carcinoma de células renales metastásico; Nivolumab; Inhibidores de puntos de control; Inmunoterapia; Seguridad; Tolerabilidad
Seguridad de nivolumab en pacientes con carcinoma de células renales metastásico: experiencia espa˜ nola en urología en la práctica clínica real Resumen Introducción y objetivo: Nivolumab es un agente inmunoterapéutico aprobado para el tratamiento de pacientes con carcinoma de células renales (CCR) avanzado tratados previamente. La experiencia en práctica clínica real, especialmente en lo referente a la aparición de reacciones adversas inmunorrelacionadas, es escasa. Presentamos la experiencia acerca de la seguridad de nivolumab en pacientes con CCR metastásico (CCRm) tratados en 9 hospitales de Espa˜ na. Material y métodos: Estudio retrospectivo, multicéntrico en pacientes con CCRm tratados con nivolumab entre 2016 y 2018. Se recogieron datos sociodemográficos y clínicos basales y las reacciones adversas relacionadas con el fármaco. Resultados: Los 26 pacientes incluidos presentaron una edad de 63,7 ± 11,5 a˜ nos. El 96% presentaba ECOG 0-1 y el 78% un riesgo MKSCC favorable/intermedio. El 73% presentaba subtipo histológico de células claras y el 30%, metástasis de inicio. La mediana de seguimiento fue de 9 meses (rango: 1-14). El 100% de los pacientes presentó una reacción adversa de cualquier grado; las más frecuentes fueron la fatiga, la fiebre y la anemia (27%). El 23% presentó una reacción adversa de grado 3. Las reacciones adversas llevaron a la suspensión del tratamiento en 3 pacientes (11%). Conclusión: En la práctica clínica real, nivolumab presenta un perfil de seguridad favorable y manejable, similar al descrito en otros estudios. © 2019 AEU. Publicado por Elsevier Espa˜ na, S.L.U. Todos los derechos reservados.
Introduction Renal cell carcinoma (RCC) is considered an ‘‘immunogenic’’ tumor. It has lacked effective therapeutic options for advanced stages of the disease for a long time. Since their development in 2005, inhibitors of vascular endothelial growth factor and mammalian target of rapamycin (mTOR) have represented a considerable advance in the treatment of metastatic RCC (mRCC). In comparison with the standard therapy which includes interferon-␣, placebo or other antiangiogenic treatment,1 these have only been effective increasing progression-free survival, but not overall survivalfor, except for mTOR temsirolimus. The advanced knowledge of the immune reactions of the host against the tumor has allowed the development of new immunotherapeutic agents, such as antibodies against immune checkpoint inhibitors.2,3 Nivolumab is a human immunoglobulin type G4 (IgG4) monoclonal antibody that binds to the programmed death 1 (PD-1) receptor and blocks its interaction with PD-L1 and PD-L2 ligands, which enhances the responses of T lymphocytes, including antitumor cells.4,5 Nivolumab is indicated for the treatment of various tumors.6 It was approved in 2016 for the treatment of adult patients with advanced RCC who had received previous systemic antiangiogenic treatment6 based on the results of the Checkmate 025 phase III study.7 In this study, nivolumab increased overall survival by
5.4 months compared to everolimus (25.0 vs. 19.6 months), an mTOR inhibitor recommended for the treatment of patients with mRCC who have progressed to treatment with vascular endothelial growth factor.1 The rates of adverse reactions with everolimus in any grade (79%) and grade 3---4 (19%), were lower (88% and 34%, respectively).7 Despite the promising results of this clinical trial, studies in real clinical practice providing data about the effectiveness and safety of nivolumab in non-selected patients would be required. Safety is especially significant regarding immune checkpoint inhibitors, since they are associated with a spectrum of immune-related adverse reactions that affect various organ systems.8---10 Although these are usually transient, they can sometimes be of moderate or severe intensity.11 Most of them can be managed safely if they are recognized, diagnosed and treated properly in the early stages of their onset.8 This is why long-term follow-up and information on these or other adverse reactions are essential to optimize the management of patients treated with nivolumab.11 There is no evidence in our country on the safety of nivolumab in mRCC in real clinical practice and is generally scarce in the literature; especially regarding the occurrence of immune-related adverse reactions.12---15 We present the experience about the safety of nivolumab in a cohort of 26 patients with mRCC treated in 9 Spanish hospitals.
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Methods Design Retrospective analysis of the data from patients with mRCC treated with nivolumab in 9 Spanish hospitals between 2016 and 2018 (n = 26). The demographic and clinical data were extracted (tumor characteristics and classification, presence of metastasis, functional status and risk factors of the patient and previous antiangiogenic treatments for advanced RCC). The functional status of the patients was classified according to the Eastern Cooperative Oncology Group (ECOG).16 For the establishment of the prognostic risk, the classification of the Memorial Sloan Kettering Cancer Center (MSKCC) was used: favorable, intermediate or poor, according to the presence of 0, 1 or 2, and 3 prognostic factors, respectively.17 The Fuhrman nuclear grading system (grades 1, 2, 3 and 4) was used for tumor classification.18 Adverse reactions were assessed at each follow-up visit. The most frequent ones related to the drug as well as others reported by the patients, were collected. Adverse reactions were classified according to the common terminology criteria for adverse reactions, version 4.0 of the National Cancer Institute (USA).19
Statistical analysis We have performed a descriptive data analysis; the categorical variables are expressed by frequencies and percentages and by the mean and the standard deviation (normal distribution) or the median and range (non-normal distribution) for the continuous variables. The relationship between the presence of grade 3 adverse reactions and the characteristics of the patients could not be statistically analyzed due to the low number of events.
Results Patients The 26 patients treated with nivolumab had a mean age of 63.7 ± 11.5 years (range: 38---79 years). Table 1 shows the demographic and clinical baseline characteristics of the patients. 92.3% of the patients (n = 24) had ECOG 0---1 and 78% had a favorable or intermediate MKSCC risk. The histological subtype clear RCC was the most frequent (73%). 30% (n = 8) of the patients presented metastasis at diagnosis; the most frequent were lung (70%). Fuhrman nuclear grade 2 was the most frequent (43%), followed by grade 3 (31%). 96.2% (n = 25) of the patients underwent nephrectomy, of whom 26.9% underwent cytoreductive surgery and 73.1% radical surgery. 73% of the patients had received only one anti-angiogenic treatment for the previous mRCC. The most widely used 1st line treatment was sunitinib (84.6%). The median number of nivolumab cycles was 15.
J. Amores Bermúdez et al. Table 1 Sociodemographic and clinical characteristics of patients. Variables Age, years, Media (SD) Median (range)
63.7 (11.5) 65.5 (38---79)
Sex, n (%) Men Women
22 (84.6) 4 (15.4)
ECOG PS, n (%) 0 1 >2
15 (57.7) 9 (34.6) 2 (7.7)
Pathological stage n (%) T1a T1b T2a T2b T3a T3b
2 3 3 2 14 2
MKSCC risk group, n (%) Favorable Intermediate Poor
6 (23.1) 15 (57.7) 5 (19.2)
Laterality, n (%) Left Right Bilateral
13 (50.0) 11 (42.3) 2 (7.7)
Location at diagnosis, n (%) Organ-confined Metastatic
18 (69.2) 8 (30.8)
Sites of metastasis, n (%)a Lung Adenopathy Bone Liver Pleural
18 14 8 4 2
Adenopathy location Retroperitoneal Mediastinal Both
(8.0) (11.5) (11.5) (8.0) (53.8) (8.0)
(69.2) (53.8) (30.8) (15.4) (7.7)
6 (42.8) 4 (28.5) 4 (28.5)
Histological subtype, n (%) Clear Papillary Mixed
19 (73.1) 4 (15.4) 3 (11.5)
Fuhrman’s nuclear grade, n (%) 2 3 4 n/a
4 11 8 3
Safety profile
Previous nephrectomy, n (%) Yes No
25 (96.2) 1 (3.8)
The median follow-up was 9 months (range: 1---14 months). Adverse reactions of any grade or grade 3---4 are shown
Number of previous antiangiogenic treatments for advanced RCC, n (%)
(15.4) (42.3) (30.8) (11.5)
Safety of nivolumab in metastatic renal cell carcinoma patients
Discussion
Table 1 (Continued) Variables 1 2 3
19 (73.1) 6 (23.1) 1 (3.8)
1st line treatment, n (%) Sunitinib Pazopanib n/a
22 (84.6) 3 (11.5) 1 (3.8)
2nd line treatment, n (%)b Axitinib Pazopanib Everolimus
3 (42.8) 2 (28.5) 2 (28.5)
RCC: renal cell carcinoma; SD: standard deviation; ECOG PS: Eastern Cooperative Oncology Group performance status; MSKCC: Memorial Sloan Kettering Cancer Center; n/a: not available. The percentages refer to valid population. a Patients could have more than one site of metastasis. b n = 7.
Table 2 Frequency of adverse reactions related to the drug during follow-up (median: 9 months). Adverse reaction, n (%) Any Fatigue Fever Anemia Cough Diarrhea Loss of appetite Skin rash Dry mouth Pruritus Dyspepsia Diplopia Dysphonia Tinnitus Hypertension Nephritis Duodenal ulcer Facial hemiparesis Hypertransaminasemia
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Any grade 20 7 7 7 5 4 4 2 2 2 2 1 1 1 1 1 1 1 1
(76.9) (26.9) (26.9) (26.9) (19.2) (15.4) (15.4) (7.7) (7.7) (7.7) (7.7) (3.8) (3.8) (3.8) (3.8) (3.8) (3.8) (3.8) (3.8)
Grade 3 7 (26.9) ------1 (3.8) --1 (3.8) --------------1 (3.8) 1 (3.8) 1 (3.8) 1 (3.8) 1 (3.8)
in Table 2. 76.9% of the patients (n = 20) presented an adverse reaction of any grade. The most frequent events were fatigue, fever and anemia (27%, n = 7). Seven grade 3 adverse reactions were reported (rate = 27%); the most frequent were loss of appetite, hypertension, nephritis and duodenal ulcer (4%, n = 1). Patients with grade 3 adverse reactions often had papillary or mixed histological subtypes and intermediate or poor MSKCC (Table 3). There were no patients with grade 4 adverse reaction. 3 (11%) patients dropped-out of treatment due to the onset of adverse reactions. These events were managed by competent urologists, in some cases with the support of the corresponding specialists.
The long-term safety and tolerability profile of the treatments available for mRCC are key aspects in the selection of the most appropriate treatment for each patient. In this sense, real clinical practice data are crucial, since they provide relevant information about safety in unselected patients. Our study shows that the safety profile of nivolumab in real clinical practice is consistent with the data available on this drug, with most adverse reactions of mild to moderate reversible severity, including grade 3. Grade 4 adverse reactions were not reported. The information available on the safety of nivolumab monotherapy in patients with mRCC derives from the studies conducted with this treatment until its approval for this indication.4,5,7 These studies show a consistent safety profile of nivolumab7,20 in the same way as it has been observed in the treatment for melanoma and non-small cell lung cancer, without new toxicities requiring special attention being identified.20 The few studies including information from real-life clinical practice in mRCC confirm the consistency of the safety profile of nivolumab even when treating unselected patients and with different follow-up lengths.12,14,15 Our study includes diverse unselected patients, showing that the safety profile of nivolumab in daily clinical practice is similar to that of patients treated with nivolumab in the Checkmate 025 Phase III study (n = 410)7 and, in general, the result of the grouped data of monotherapy treatment for different tumors in 2578 patients.6 The percentage of patients with any adverse reaction of any type in our study (77%) was practically the same as in the Phase III study (79%), while the rate of grade 3---4 adverse reactions was slightly higher (27% versus to 19% in the phase III study). However, we must highlight that all adverse reactions in our study were grade 3. The most frequent adverse reactions associated to this drug in our series were fatigue, fever and anemia, all with an incidence of 27%, and none of these were grade 3. Fatigue was also the most frequent event in the Checkmate 025 study, with a fairly higher incidence (33%: 3% of grade 3---4). However, the incidence of anemia was lower (8%) and there were no cases of fever, an adverse reaction which had been previously classified as ‘‘frequent’’.6 We must remember that anemia could also be a result to the advanced stage of RCC, rather than constituting an adverse reaction to the treatment. In addition to fatigue, the most frequent adverse reactions in the Checkmate 025 study were nausea and pruritus (both with an incidence of 14%, none of grade 3---4).7 In our series of patients, nausea was not reported, and the incidence of pruritus was also somewhat lower (8%, none of grade 3). It should be noted that the Checkmate 025 study only shows the adverse reactions present in ≥10% of the patients of both treatment arms, which may affect the adverse reactions reported in the group treated with nivolumab. This is probably why adverse reactions classified as ‘‘frequent’’ such as dry mouth or hypertension, present in our series in 2 patients (8%) and one patient (4%), respectively, are not mentioned in this study. Nearly 20% of our patients presented cough, in one case (4%) of grade 3. The incidence of this adverse reaction
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Table 3
Characteristics of patients with grade 3 adverse reactions.
Grade 3 adverse reaction Age (years) Sex
Location
Nephrectomy
Subtype
ECOG MSKCC
Previous lines 1st line treatment
2nd line treatment
Hypertension, nephritis Cough, duodenal ulcer Facial hemiparesis Hypertransaminasemia Loss of appetite
Organ-confined Organ-confined Organ-confined Organ-confined Organ-confined
Radical Radical Radical Radical Radical
Papillary Mixed Clear Papillary Clear
0 1 0 1 0
1 1 2 2 1
----Everolimus Everolimus ---
59.0 52.0 65.0 72.0 33.0
Male Female Male Female Male
Intermediate Poor Intermediate Intermediate Favorable
n/a Sunitinib Sunitinib Sunitinib Sunitinib
ECOG PS: Eastern Cooperative Oncology Group performance status; MSKCC: Memorial Sloan Kettering Cancer Center; n/a: not available.
J. Amores Bermúdez et al.
Safety of nivolumab in metastatic renal cell carcinoma patients classified as ‘‘very frequent’’6 was 9% in the Checkmate 025 study. Loss of appetite, present in 15% of the patients (in one case [4%] of grade 3), had a similar incidence in the Checkmate 025 study (12%), with 2 cases (1%) of grades 3---4. Strikingly, one of the patients in our series developed a gastroduodenal ulcer, an adverse reaction classified as ‘‘rare’’. The most frequent immune-related adverse reactions (>10%) were cutaneous (27%, with 8% skin rash and 8% pruritus) and diarrhea or colitis (15%), none of them grade 3. The incidence of this type of adverse reactions in the Checkmate 025 study was similar: 24% (14% pruritus and 10% skin rash) and 12%, respectively, with an incidence of grade 3---4 of 1% in both cases. Other potentially immune-related adverse reactions in our series of patients were peripheral neuropathy (diplopia, dysphonia, tinnitus and facial hemiparesis) and nephritis, all of them present in only one patient (4%). Adverse reactions led to treatment withdrawal of patients with similar percentages in both studies (11% vs. 8% in the Checkmate 025 study). Regarding the interpretation of our safety results in real clinical practice with respect to those reported in the Checkmate 025 study, we must consider the sociodemographic and clinical differences among patients, as well as the length of follow-up. In the first case, both populations were roughly similar, except for the ratio of patients with clear cell histological subtype or metastasis, which was lower in our series compared with the Checkmate 025 study (73 vs. 100% and 31 vs. 83%, respectively). The percentage of patients who had received one or two previous treatments was similar (73 vs. 72% and 23 vs. 28%, respectively). Regarding follow-up, the median in our series was 9 months (range: 1---14) compared to the minimum 14 months of patients treated with nivolumab in the Checkmate 025 study. The studies including different types of tumors had a follow-up of 28 months, which contributed to include events occurring in the longer term. However, the most frequent adverse reactions (≥10%) in these studies were generally the same as those observed in the Checkmate 025 study and ours: fatigue (30%), rash (17%), pruritus (13%), diarrhea (13%) and nausea (12%).6 Two studies in real clinical practice with mRCC patients have confirmed the safety profile reported in the Checkmate 025 study: one of them included 528 patients with a 13-month follow-up period,12 and the other, 389 patients enrolled in the Italian cohort of the EAP (Expanded Access Program), with a follow-up of 7 months.15,21 In addition to the limitations inherent to the retrospective nature of our study, the low number of patients constitutes a relevant limitation, since it enhances the sensitivity of the occurrence of an event (onset of an adverse reaction), which results in higher rates than those observed in studies with larger cohorts of patients (Checkmate 025). On the other hand, the great number of patients in this study (Checkmate 025) provides information on rare adverse reactions that have not been captured in our study. With regards to immune-related adverse reactions, some of them --- which have been widely described, such as colitis, cutaneous or endocrine --- may have been adequately collected. However, in the case of others less known --- which have not been collected in clinical trials but in the daily clinical practice, such as musculoskeletal problems --- may have not been properly reported.22
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Conclusion Our experience in real clinical practice shows that nivolumab has a favorable and manageable safety profile, similar to the data described in the pivotal study, in studies in other tumors and other studies in real clinical practice.
Conflicts of interest The authors declare that they have no conflicts of interest.
Acknowledgements The authors would like to thank Beatriz Viejo for her support and help in writing and editing this document.
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