Discussion

sRCC typically portends a poor prognosis as demonstrated by a review of clinical data presented in table 2. This may, in part be due to high PD-L1 expression on sRCC cells which has been independently associated with poor outcomes in renal cell cancer.12 In prior studies, BAP1 loss was associated with high tumor grade, sarcomatoid differentiation and poor outcomes, as noted in our patient.13 14 In RCC, BAP-1 mutations have been identified in approximately 15% of patients with RCC and was noted to enhance mesenchymal–epithelial transition, which could be one reason why our patient presented with metastatic disease within 3 months of diagnosis.15 16 The Checkmate 214 trial examined the safety and efficacy of anti-PD-1 with anti-CTLA4. A significant improvement in OS was noted in all RCC patients after treatment with ipilimumab and nivolumab compared with sunitinib (median not reached vs 26 months, HR 0.63).17 Among patients with sarcomatoid differentiation, the rate of complete response (CR) was 18.3% with nivolumab plus ipilimumab versus 0% with sunitinib with superior OS in the immunotherapy arm irrespective of PD-L1 expression. However, significant toxicity was noted with ipilimumab and nivolumab, with 46% of patients experiencing grade 3–4 toxicity. Even though the results with immunotherapy are promising for sRCC compared with historical data, a majority of patients do not respond and progression is inevitable, thus development of novel treatment strategies is urgently needed.

Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and PD-1 are inhibitory receptors on T cells that limit T cell activation and function. These proteins act through distinct mechanisms to block T cell activation. CTLA-4 is expressed after initial T cell activation and acts to sequester ligands B7-1 and B7-2 (CD80, CD86) that are required for signaling through the costimulatory receptor CD28.18 Blockade of CTLA-4 results in enhanced activation of primary T cells and clonal expansion of nascent CD8+T cell clones.18 Anti-CTLA4 antibodies with heavy chains capable of fixing complement may also eliminate inhibitory T cell subsets, such as regulatory foxP3+CD4+T cells, from the tumor microenvironment.19 In contrast, therapies targeting the PD-1/PD-L1 axis act on CD8+T cells that have undergone initial activation but acquired functional attenuation due to chronic exposure to antigen through a process termed T cell exhaustion.20 Thus, although the two therapeutic strategies both fall under the purview of immune checkpoint inhibition, they act through distinct mechanisms to selectively potentiate activation of naïve (anti-CTLA-4) or exhausted (anti-PD-1/PD-L1) CD8+T cells. A possible explanation for the secondary responsiveness to ipilimumab observed in this patient is that progression of RCC results in development of neoantigens that can be recognized by naïve T cells in a manner facilitated by anti-CTLA-4.

The use of ipilimumab is limited to four doses when given in combination with nivolumab given concerns for significant autoimmune toxicities.21 Checkmate 016 evaluated the role of intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (N3I1), nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1I3) or nivolumab 3 mg/kg plus ipilimumab 3 mg/kg (N3I3) every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks until progression or toxicity in RCC patients.22 The incidence of grade 3/4 AE was significant with N1I3 and N3I3 dosing and hence the regimen used in our patients is FDA approved.

The use of ipilimumab with nivolumab a salvage therapy has been reported in patients with melanoma, with approximately 50% of patients demonstrating disease control.23 Unfortunately, 68% of these patients experienced clinically significant toxicity resulting in 40% of patients discontinuing therapy.

Salvage ipilimumab and nivolumab has been found to be safe and effective in immune checkpoint inhibitors (ICI) refractory melanoma and ccRCC patients.23–25 The TITAN trial that was discussed at European Society of Medical Oncology (ESMO) 2019 evaluated the role of salvage ipilimumab in combination with nivolumab for patients with stable disease/progressive disease on single agent nivolumab and noted a 10 per cent salvage rate with ipilimumab. This study is different from our approach as our patient had received prior ipilimumab and nivolumab, salvage ipilimumab was added when the patient had progressed on single agent nivolumab. In the TITAN trial, none of the patients had gotten upfront ipilimumab. In the TITAN trial, the CR rate was also significantly lower than checkmate 214 and with immature OS data, suggesting that upfront ipilimumab may be warranted for eligible patients. Another retrospective study evaluated the use of ipilimumab and nivolumab as salvage therapy in patients with clear cell mRCC refractory to immunotherapy therapy combinations and a 40% partial response rate was noted.24 It would also be worth further exploring the role of Ipilimumab with a dose of 3 mg/kg as salvage therapy if toxicity permits. Further studies are needed to determine which sRCC patients are appropriate for salvage ipilimumab with progression on nivolumab monotherapy. It is also unknown as to whether BAP1 loss in RCC defines a cohort that is immune responsive. Further, the optimal frequency and dose of ipilimumab treatment needs to be established.

Here, we report the first case of reinvigoration of responses in an sRCC patient undergoing nivolumab maintenance monotherapy with the addition of ipilimumab. This suggests that ipilimumab could be used to salvage maintenance nivolumab in sRCC and indicates that enhancing activation of naïve T cell subsets could be an important mechanism to engage effective immune responses in sRCC. Further studies are needed to evaluate this approach.