Safety and efficacy of nivolumab as a second line therapy in metastatic renal cell carcinoma: a retrospective chart review

Aim To assess diseases outcomes and tolerability of real-life second-line nivolumab in a series of metastatic renal cell carcinoma (mRCC) patients. Methods This retrospective chart review involved prospectively monitored patients (named patient program) treated with second-line nivolumab for mRCC at the University Hospital Centre Zagreb from February 2016 to March 2018. Results The study enrolled 30 patients, 5 of whom (16.7%) had a complete response. The mean ± standard deviation therapeutic response time to nivolumab treatment was 14.07 ± 8.92 months, with a minimum treatment duration of 2 months and a maximum of 24 months. The median duration of therapy was 17 months (mean: 15.8 months; range: 3-24 months), and 50% (n = 15/30) of patients remained alive at the end of follow up. The most common adverse events associated with nivolumab were fatigue (26.67%; n = 8/30), anemia (10.0%; n = 3/30), adrenal insufficiency (6.67%; n = 2/30: G1 = 1, G2 = 1), grade 2 pneumonitis (6.67%; n = 2/30), grade 2 neuropathy (6.67%; n = 2/30), rash (6.67%; n = 2/30: G1 = 1, G2 = 1), and hepatitis (3.33%; n = 1/30). Conclusion The present study indicates acceptable patient responses and tolerability of nivolumab in mRCC.

Each year, approximately 337 000 new cases of renal cell carcinoma (RCC) are diagnosed globally, with 143 000 deaths (1). Thirty-three percent of the patients who undergo surgical intervention relapse and additional 33% develop metastases upon initial diagnosis (2,3). A total of 75%-85% of primary kidney malignancies belong to the group of clear cell RCCs, while the remaining histologically diverse tumors are categorized as non-clear cell RCC. Nonclear cell RCCs differ from clear cell RCCs in pathologic and histologic features and clinical presentation (3). Early diagnosis of RCC is crucial as timely surgical intervention can prolong the patient's life (5-year survival rate of 93%). Unfortunately, a third of the patients already have advanced disease at diagnosis and 10%-20% of them experience a relapse (4)(5)(6)(7).
Over the past few years, RCC has been successfully treated with endothelial growth factor receptor tyrosine kinase (VEGF TKI) and mammalian target of rapamycin inhibitors (mTORi) (8). VEGF TKIs are highly effective and can safely be used for several years. However, the median overall survival (22-29 months) suggests that there is still room for improvement (9). Therefore, it is paramount that clinicians have an expert understanding of immunotherapy, as most patients with advanced RCC undergo multiple therapies over the course of their disease (10).
Nivolumab is a PD-1 checkpoint inhibitor that restores the pre-existing antitumor immune response by selectively blocking the interaction between PD-1 receptors on T-cells and PD-1 ligands, PD-L1 and PD-L2, on tumor cells and antigen presenting cells. A 2012 phase I trial demonstrated nivolumab's antitumor activity and manageable safety profile in metastatic RCC (11). In 2015, nivolumab was approved (CheckMate 025) by Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as a second-line therapy for advanced RCC patients with prior anti-angiogenic therapy, and in 2018 by the EMA as the first-line therapy for patients with intermediate-and poorrisk advanced RCC (12,13).
Since approval, a number of clinical trials have been conducted to further assess the safety, tolerability, and efficacy of nivolumab, or the combination of nivolumab with another antitumor therapeutic agent, in RCC treatment (14)(15)(16). We aimed to assess disease outcomes and tolerability of real-life second-line nivolumab in a series of mRCC patients. Our primary aim was to evaluate the dose response with regards to progression-free survival (PFS), overall survival (OS), and time-to-treatment failure (TTF). The second-ary aim was to assess the relative safety of nivolumab as a second-line therapy by assessing nivolumab-related adverse events.

PAtiENts AND MEthoDs
In February 2019, we retrospectively reviewed the charts of patients with an indication for treatment with nivolumab for mRCC managed between February 2016 and March 2018 at the Clinical Hospital Centre Zagreb. Patients were identified through the Center's electronic health record database, and all patients who received nivolumab were included. Patient data were collected in compliance with all ethical and regulatory standards regarding patient confidentiality.
The study recruited all patients who took part in a named patient program according to the EMA's medication registration criteria. Heng and MSKCC/Motzer score models for predicting survival were used as inclusion criteria and for stratification of patients into a favorable-risk group, intermediate-risk group, and poor-risk group. Treatment duration was defined as the period from the initial treatment start date to the date of the last treatment cycle. Response to therapy was defined as either complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) according to RECIST (17). Patients in whom it was impossible to determine whether they had progression, regression, or stable disease were classified as "mixed response" patients ("modified RECIST"). The PFS was defined as the time in months between the initiation of therapy to progression of disease or death, whereas OS was defined as the time in months from the initiation of therapy to death. Time-to-treatment failure was defined as the interval from the initiation of therapy to its premature discontinuation, which could have ensued due to different reasons, such as cancer progression, adverse events, patient choice, or patient death. The patients were re-assessed at regular scheduled visits at 2, 3, 6, 9, 12, 15, 18, and 24 months.
Nivolumab was administered at a standard dose of 3 mg/ kg every two weeks for up to two years. Patients were asked to visit their oncologist every three months for control and consultation. The follow-up visits included laboratory tests, multi-slice computed tomography (MSCT) of the chest, abdomen, and pelvis, and bone status. Patients with musculoskeletal pain underwent a bone scan. The treatment duration ranged from 3 months (shortest) to 24 months (longest).  All relevant data were collected during treatment and were used to determine the baseline characteristics and adverse events observed during nivolumab therapy. Descriptive statistical analysis was performed using the R programming language, v.3.4.0 (The R Foundation for Statistical Computing, Vienna, Austria) to evaluate the differences in patients' safety and therapeutic response to nivolumab.

therapeutic response
The mean ± standard deviation response time to nivolumab treatment was 14.07 ± 8.92 months, with a minimum response time of 2 months and a maximum of 24 months. The median duration of therapy was 17 months (mean: 15.8 months; range: 3-24 months). The therapeutic response (stable disease-partial response-complete response, disease progression) is shown in Figure 1 and OS, PFS, and TTF in Figure 2. Patients who were treated with nivolumab for 6 to 12 months, in spite of radiological progression, were ECOG 0-1 and were still alive at the last follow-up visit, while 5 out of 30 (16.7%) had a complete response. At 12 months of follow up, OS was 90% (n = 27/30), PFS 43% (n = 13/30), and TTF 53% (n = 16/30). At 24 months, OS was still not reached as 50% (n = 15/30) of the patients were alive at the last follow-up visit, TTF was 50% (n = 15/30), and PFS remained 43% (n = 13/30) (Figure 2).

DisCussioN
Our findings show acceptable patient response and manageable safety profile of nivolumab for RCC, which is consistent with the drug's recent approvals in this indication by the regulatory agencies. The incidences of immune related adverse events in this study were comparable with those described in the literature (18,19). Furthermore, nivolumab with its mean duration of treatment of 14.07 ± 8.92 months appears to be a good second-line therapy option for patients who also had a long response (>1 year) time to TKI in the first line therapy.
In the last few years advanced RCC has been successfully treated by combinations of immunooncologic therapies. However, the optimal drug sequential therapy for every patient remains to be found. The outcome of mRCC has improved with the advancement of targeted therapies (20). There are seven targeted therapies currently available for clear cell RCC: VEGFR TKIs (sorafenib, sunitinib, pazopanib, and axitinib); VEGF-directed monoclonal antibody bevacizumab (approved in combination with IFN); and mTORi (everolimus and temsirolimus). Although these agents achieved a positive impact, long-term responders are rare (21). High-dose IL-2 is the only approved agent to produce complete durable responses, but hospitalization and intense monitoring are still required (22).
In one of the first trials with nivolumab on 236 patients who received the drug every two weeks (0.1-10 mg/kg), responses were identified in NSCLC (18%), melanoma (28%), and RCC (27%), many of which were durable (10). Since the FDA's and EMA's approval of nivolumab as a second-line agent for therapy of advanced RCC, a number of clinical trials and studies have confirmed its effectiveness and safety in that indication (18,19,23,24). ChekMate 025 trial, conducted during more than 5 years in metastatic clear cell RCC patients, found that nivolumab was a better treatment choice than everolimus, with a median OS of 25.8 months vs 19 months (25). Nivolumab also showed improved PFS.
The limitations of this study include a small study sample and potential information and selection bias. Additionally, we did not use cabozantinib, as it is not reimbursed by the Croatian Health Insurance Fund. Despite such potential weaknesses, we believe that our results verify the current direction of investigations into the effectiveness and safety of nivolumab, thus reaffirming this drug's potential to become the standard treatment for patients with advanced RCC with prior antiangiogenic therapy (12,24). Since immunotherapy in the second-line treatment demonstrated good results in metastatic clear cell RCC patients, a combination of immuno-immuno therapy (nivolumab/ipilimumab) or immuno (pembrolizumab or avelumab) and TKI (axitinib) therapy is increasingly being used as the firstline treatment (26).  . the severity of adverse events that occurred during nivolumab treatment for metastatic renal cell carcinoma. G -grade Competing interests MG: Speaker/advisory board fees (BMS, Pfizer, Novartis, Astellas, Sanofi, Janssen, Roche, Sandoz, Amgen, Bayer, PharmaSwiss, MSD, Alvogen); non-financial support for drugs (BMS, Roche, Janssen); ZAG: Speaker fees for Novartis, Sanofi; RL: Speaker/advisory board fees for Astellas, Roche, Sandoz, MSD. RL is a member of the Editorial Board of the Croatian Medical Journal. To ensure that any possible conflict of interest relevant to the journal has been addressed, this article was reviewed according to best practice guidelines of international editorial organizations. All authors have completed the Unified Competing Interest form at www.icmje.org/ coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.