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Real-World Safety and Efficacy of Nivolumab for ≥ 2Nd Line Treatment of Metastatic Renal Cell Carcinoma: a Retrospective Cohort Study in Croatia, Hungary, and Malta

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Real-World Safety and Efficacy of Nivolumab for ≥ 2Nd Line Treatment of Metastatic Renal Cell Carcinoma: a Retrospective Cohort Study in Croatia, Hungary, and Malta 208 Neoplasma 2021; 68(1): 208–215 doi:10.4149/neo_2020_200512N519 Real-world safety and efficacy of nivolumab for ≥ 2nd line treatment of metastatic renal cell carcinoma: A retrospective cohort study in Croatia, Hungary, and Malta Eduard VRDOLJAK1,*, Claude MAGRI2, Marija GAMULIN3, Lidija BOŠKOVIĆ1, Tomislav OMRČEN1, Žarko BAJIĆ4, Tamas DIENES5, Lajos GECZI5 1Department of Oncology, University Hospital Split, School of Medicine, University of Split, Split, Croatia; 2Mater Dei Hospital, Triq Dun Karm, L-Imsida, Malta; 3Department of Oncology, University Hospital Center Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia; 4Research unit “Dr. Mirko Grmek”, Psychiatric Hospital Sveti Ivan, Zagreb; Croatia; 5National Institute of Oncology, Budapest, Hungary *Correspondence: [email protected] Received May 12, 2020 / Accepted August 12, 2020 The objective of our study was to assess the real-world safety and efficacy of nivolumab in the second- or later-line treat- ment of metastatic renal cell carcinoma (mRCC). We conducted a multicenter, retrospective, observational study of real- world data from patients who were treated with nivolumab under a patient expanded access program from 2015 to 2017 in Croatia, Hungary, and Malta. The primary safety endpoint was the discontinuation of therapy because of adverse events. The primary efficacy endpoint was overall survival (OS). We collected data from 87 patients with a median (interquartile range (IQR)) age of 63 (57-68) years, and 21% were females. The median (IQR) follow-up was 11 (5-31) months. Treatment was discontinued because of toxicity in 4 (5%) patients. Four (5%) patients experienced treatment-related adverse events of grade 3 or 4. The OS was 18.0 (95% CI: 11.0 to 28.6) months, and the PFS was 8.5 (95% CI: 4.9 to 12.1) months. Our study indicated a good safety and efficacy profile of nivolumab in the second- or later-line treatment of mRCC patients in a real- world clinical practice environment, which is comparable with the findings of the registrational trial. Key words: metastatic renal carcinoma, PD-1 immune checkpoint inhibitor, nivolumab, immunotherapy An understanding of the mechanisms involved in the used in therapy for a variety of cancers in everyday practice, carcinogenesis of clear cell renal carcinoma has led to the mRCC included [12]. Nivolumab is a human immunoglob- development of targeted therapies directed against vascular ulin G4 programmed death-1 immune checkpoint inhibitor endothelial growth factor [1–7]. With optimal utilization antibody that selectively blocks the interaction between PD-1 of such agents throughout multiple lines of therapies, the and its ligands PD-L1 and PD-L2, a mechanism that usually median overall survival time of metastatic renal cell carci- leads to the inhibition of cellular immune response [13]. By noma (mRCC) patients more than doubled: from 12 months inhibiting this inhibition, nivolumab can enhance antitumor in the cytokine era to 30 months in tyrosine kinase inhib- T-cell activity [14]. Based on the practice-changing results of itor (TKI) era [1–8]. Unfortunately, despite an observed a randomized phase III study (CheckMate 025), nivolumab benefit associated with TKIs in terms of progression-free is now widely used as a standard second- or later-line treat- survival (PFS) and overall survival (OS), almost all patients ment option (after first-line TKI therapy) in the treatment of with mRCC eventually experience disease progression and mRCC [15]. Expanded-access programs generally apply less ultimately die, highlighting the need for more effective stringent entry criteria than clinical trials and allow patients treatment options. Multiple possible immune resistance who have no access to, or who are ineligible for, clinical trials mechanisms have been described in tumor development the opportunity to receive a new drug therapy prior to its [9, 10]. The most promising mechanism from a treatment approval. The findings from expanded-access programs point of view is the inhibition of immune checkpoints [11]. complement those of regular clinical trials by providing The recent understanding of these immune mechanisms insight into real-world treatment patterns, safety, and effec- has resulted in the generation of many antibodies directed tiveness in a broad spectrum of community-based cancer against immune checkpoint receptors that are already widely patients, including those with poor prognosis. This retro- NIVOLUMAB IN mRCC 209 spective analysis of the nivolumab expanded access program nine in mg/dl), AST ≤3×ULN, ALT ≤3×ULN, total bilirubin data examines treatment outcomes among study partici- ≤1.5×ULN (except patients with Gilbert Syndrome who can pants in Croatia, Hungary, and Malta, countries with some have total bilirubin <3.0 mg/dl). of the highest rates of RCC in the world, as well as histori- The exclusion criteria were ECOG performance status ≥3; cally inferior oncological outcomes and limited second- and life expectancy of <6 weeks; active brain or leptomeningeal third-line treatment options compared with those in other metastasis; carcinomatous meningitis; ocular melanoma; parts of Europe [16–19]. known or suspected autoimmune disease; prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CT137, or Patients and methods anti-CTLA-4 antibodies including ipilimumab or any other antibody or drug specifically targeting T cell co-stimulation or Study design. We conducted a multicenter, retrospective, checkpoint pathways; prior treatment in any nivolumab trial, observational study of real-world data of patients who were including prior treatment on either arm of nivolumab studies treated with nivolumab in an expanded-access program from CA209057 or CA209026; interstitial lung disease that was November 11, 2015 to January 2, 2017 at the Department symptomatic or may interfere with the detection or manage- of Oncology, Clinical Hospital Center Split, Split, Croatia; ment of suspected drug-related pulmonary toxicity; other Department of Oncology, University Hospital Center Zagreb, active malignancy requiring concurrent intervention; known Zagreb, Croatia; National Institute of Oncology, Budapest, alcohol or drug abuse; known history of testing positive for Hungary; and Mater Dei Hospital, Triq Dun Karm, L-Imsida, human immunodeficiency virus (HIV) or known acquired Malta. The study protocol was evaluated and approved by the immunodeficiency syndrome (AIDS); history of severe ethics committees of all participating institutions. Patients hypersensitivity reactions to other monoclonal antibodies; who were alive at the time of data collection signed the history of allergy or intolerance to program drug compo- informed consent forms. Before the analysis, we anonymized nents or polysorbate-80-containing infusions; pregnancy all the data and concealed the patients’ identities to everyone and breastfeeding; and prior malignancy active within the but the patients’ oncologists. We performed the study in previous three years except for locally curable cancers that accordance with the World Medical Association Declaration have been apparently cured, such as basal or squamous cell of Helsinki of 1975, as revised in 2013, and the International skin cancer, superficial bladder cancer, or carcinoma in situ Conference on Harmonization Guidelines on Good Clinical of the prostate, cervix or breast. Practice [20]. The study was sponsored by Bristol-Myers Sample type and required sample size. We did not select Squibb. We did not pre-register the protocol. the sample but rather included the total targeted population. Study population. The inclusion criteria were age ≥18 Therefore, we did not calculate the required sample size in years, histologically confirmed advanced or metastatic advance. RCC with a clear cell component, Eastern Cooperative Endpoints. The primary safety endpoint was the discon- Oncology Group (ECOG) performance status (PS) ≤2, and tinuation of therapy because of adverse events. The secondary treatment with at least one prior anti-angiogenic therapy safety endpoints were incidence of grade 3 or 4 treatment- regimen (including but not limited to, sunitinib, sorafenib, related and immune-mediated adverse events according to pazopanib, axitinib, tivozanib, and bevacizumab) in the the Common Terminology Criteria for Adverse Events v4.0. advanced or metastatic setting. Prior cytokine therapy (e.g. The primary efficacy endpoint was overall survival (OS). The IL-2, IFN-a), vaccine therapy, or treatment with cytotoxic secondary efficacy endpoints were progression-free survival was also allowed. Patients had to have measurable disease by (PFS), best response, overall response rate (ORR) defined as CT or MRI per the RECIST 1.1 criteria; radiographic tumor a partial or complete response, disease control rate (DCR) assessments performed within 28 days of the first dose of the defined as a partial or complete response or the stabiliza- program drug. Prior targeted therapy had to be completed at tion of disease, time from the introduction of nivolumab least 4 weeks prior to the program drug administration, and to response in months (TTR), and the duration of response all adverse events had to have either returned to the baseline (DOR) in months. condition or stabilized. Prior radiotherapy or radiosurgery Treatment. Nivolumab (Opdivo, Bristol-Myers Squibb) had to be completed at least 2 weeks prior to the first dose of was administered at a dosage of 3 mg/kg body weight via the program drug. 60-minute intravenous infusions
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