Response to combined ipilimumab and nivolumab after development of a nephrotic syndrome related to PD-1 monotherapy
High response rates of metastatic melanoma have been reported upon immune checkpoint inhibition by PD-1 blockade alone or in combination with CTLA-4 inhibitors. However, the majority of patients with a primary resistance to anti-PD-1 monotherapy is also refractory to a subsequent combined checkpoint inhibition. In BRAF wildtype patients with a primary resistance to PD-1 inhibitors, therapeutic options are therefore limited and immune-related adverse events (irAE) have to be taken into consideration when discussing a subsequent immunotherapy.
We report the case of a 68-year-old male patient with metastatic melanoma who experienced an acute renal failure with nephrotic syndrome due to a minimal change disease developing after a single dose of the anti-PD-1 antibody pembrolizumab. A kidney biopsy revealed a podocytopathy without signs of interstitial nephritis. Renal function recovered to almost normal creatinine and total urine protein levels upon treatment with oral steroids and diuretics. Unfortunately, a disease progression (PD, RECIST 1.1) was observed in a CT scan after resolution of the irAE. In a grand round, re-exposure to a PD-1-containing regime was recommended. Consensually, a combined immunotherapy with ipilimumab and nivolumab was initiated. Nephrotoxicity was tolerable during combined immunotherapy and a CT scan of chest and abdomen showed a deep partial remission (RECIST 1.1) after three doses of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg).
This case illustrates that a fulminant response to combined checkpoint inhibition is possible after progression after anti-PD-1 monotherapy and a severe irAE.
KeywordsPD-1 Immune-related adverse event Minimal change disease Ipilimumab Nivolumab
In prospective clinical trials response rates of up to ~ 40% to anti-PD-1 monotherapy and ~ 60% for combined checkpoint inhibition (ipilimumab plus nivolumab) have been reported in patients with advanced or metastatic melanoma . Unfortunately, treatment options for BRAF wildtype patients resistant to anti-PD-1 monotherapy are limited. The majority of such patients are also refractory to subsequent combined checkpoint inhibition [2, 3]. In addition, severe immune-related adverse events (irAE) related to monotherapy and possible irAE during subsequent immunotherapy must be taken into consideration when counselling these patients. Here, we report a case with a rare and severe renal irAE due to pembrolizumab monotherapy and a deep response to subsequent, well-tolerated ipilimumab and nivolumab.
During irAE treatment, S100 serum levels increased significantly and a computed tomography (CT) scan of chest and abdomen 2 months after the single dose of pembrolizumab showed diesease progression (PD, RECIST 1.1) (Fig. 1). A grand round recommended re-exposure to a PD-1-based immunotherapy due to lacking effective therapy alternatives. The recommendation was discussed with the patient including the risk of an immunotherapy-related terminal dialysis-dependent renal insufficiency. Finally, a combined checkpoint inhibition with ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) was initiated. Proteinuria and blood pressure were monitored weekly. After two applications of the combined immunotherapy, creatinine levels increased to values ~ 2 mg/dl and the patient once again showed massive proteinuria (total protein 18,200 mg/l) (Fig. 2). Fortunately, there were no signs of peripheral edema and his body weight remained stable. To curtail proteinuria, oral treatment with the ACE inhibitor ramipril was escalated to 5 mg qd.
Discussions and conclusions
The frequency of renal adverse events related to anti-PD-1 therapy is very low [4, 5, 6]. Interstitial nephritis with predominant tubulointerstitial injury is the most common presentation of an acute kidney injury related to anti-PD-1 therapy [4, 7, 8], whereas an acute renal failure with nephrotic syndrome due to a minimal change disease is rare. So far, only two cases of nephrotic syndrome with minimal change disease secondary to therapy with an anti-PD-1 antibody have been reported [9, 10]. Both patients received pembrolizumab for Hodgkin’s lymphoma (HL). In contrast to HL, malignant melanoma is not known to induce minimal change disease itself [11, 12, 13]. Thus, the acute kidney injury in our patient was related to pembrolizumab most likely. Consistent with the two cases reported and guidelines for managing irAE, immunotherapy was stopped and both creatinine as well as proteinuria improved after administering systemic glucocorticoids. In case of an immune-related acute kidney injury grade 3 according to the Common Toxicity Criteria of Adverse Events (CTCAE) treatment with methylprednisolone 0,5–1 mg/kg daily is recommended and creatinine levels should be monitored every 2 to 3 days . In case of unclear clinical findings a kidney biopsy and a nephrology consultation are warranted .
Most melanoma patients resistant to nivolumab or pembrolizumab monotherapy are also refractory to a subsequent combined immunotherapy with ipilimumab plus nivolumab [2, 3]. However, there are case reports of fulminant responses to combined checkpoint inhibition after failure of anti-PD-1 monotherapy despite unfavorable predictive factors such as elevated lactate dehydrogenase (LDH) . Besides, there are reports that immunotherapy is safe in patients with an impaired renal function due to other underlying diseases . In a process of participatory decision-making considering possible risks (e.g. dialysis-dependent renal failure) and alternative treatment options (PD-1 monotherapy with nivolumab, CTLA-4 monotherapy with ipilimumab or chemotherapy with dacarbazine), combined checkpoint inhibition with ipilimumab and nivolumab was initiated and led to a deep response without new toxicites.
This unique case demonstrates that a response to combined checkpoint inhibition is possible after disease progression after anti-PD-1 monotherapy and that application of an anti-PD-1-based treatment after a severe irAE during anti-PD-1 monotherapy might be worthwhile. Keeping in mind that a response to ipilimumab plus nivolumab is still rare after disease progression after anti-PD-1 monotherapy [2, 3], this treatment sequence should only be chosen in case of lacking effective treatment alternatives such as a targetable driver mutation.
VG, JW, FG and AG assessed and confirmed the accuracy of the details relating to the patient’s oncologic history and treatment. VG and BS prepared figures. All authors took care of the patient. All authors contributed to the writing and revising of the manuscript. All authors read and approved the final manuscript.
No specific funding was received.
Ethics approval and consent to participate
Consent for publication
Formal consent for anonymous publication of retrospective data from routine care is not required by local laws.
Valerie Glutsch reports travel support from Novartis, Pierre Fabre Pharmaceuticals, Bristol-Myers Squibb (BMS) and Merck Sharp & Dohme (MSD).
Judith Weber reports travel support from BMS and MSD.
Anja Gesierich reports advisory roles for BMS, MSD, Novartis, Roche, Pfizer, Sanofi Genzyme, has received honoraria from MSD and BMS, and travel support from BMS, MSD, Novartis and Roche.
Bastian Schilling reports advisory roles for or has received honoraria from Pierre Fabre Pharmaceuticals, Incyte, Novartis, Roche, BMS and MSD, research funding from BMS, Pierre Fabre Pharmaceuticals and MSD, and travel support from Novartis, Roche, BMS, Pierre Fabre Pharmaceuticals and Amgen.
All other authors declare no conflicts of interest.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.