Merkel cell carcinoma (MCC) is a rare, aggressive cancer of the skin, originating in neuroendocrine (NE) cells and associated with Merkel cell polyoma virus (MCPyV) in 50%–80% of cases and UV-induced mutagenesis in the remaining cases, with some exceptions.1 2 When present, expression of MCPyV T antigens is required for MCC tumor cell survival, suggesting it is a target for immunotherapy.3 UV-induced MCC is associated with high tumor mutational burden (TMB),2 a finding that also supports the use of immunotherapy. MCC treatment consists of surgery, adjuvant radiotherapy and/or immune checkpoint inhibitor therapy in metastatic disease.4 5

Avelumab, an antiprogrammed death ligand 1 (PD-L1) monoclonal antibody, was FDA approved for use in MCC in March of 2017 (it is also approved in the EU and Japan) based on data from the JAVELIN Merkel 200 trial in which the overall response rate was 33%.6 7 Responses were observed early and duration ranged from 2.8 to 23.3+ months with 86% of responses being durable for 6 months or longer. Responses were observed in patients regardless of PD-L1 tumor expression or presence of MCPyV.8 Avelumab is thus the first therapeutic agent specifically approved for use in this indication, independent of line of treatment.

The interleukin-15 (IL-15) superagonist N-803 (also known as ALT-803)9 is an experimental compound comprizing a human IL-15 variant bound to a dimeric human IL-15 receptor α sushi domain/human IgG₁ Fc fusion protein that acts as a growth and activation factor for natural killer (NK) cells as well as effector and memory T cells targeting both the innate and adaptive immune systems.10 11 N-803 alone or combination with an anti-PD-L1 antibody has been shown to elicit robust antitumor immune responses and prolonged survival in tumor-bearing mice.12 13 N-803 has also been shown to increase PD-L1 expression both in vitro14 and in breast-tumor-bearing mice15; and it has been suggested that this may allow lymphocytes to become targets of anti-PD-L1 therapy.

Current data support the use of combination immunotherapy of N-803 with PD-1/PD-L1 inhibitors. Encouraging phase 1b/2 clinical trial data indicate the combination of anti-PD-1 nivolumab and N-803 may be effective in treating checkpoint inhibitor-relapsed patients by enhancing NK and T-cell attack while checkpoint inhibitors prevent exhaustion.16 Several clinical trials are underway to determine efficacy of N-803 in combination with haNK (genetically engineered with the high binding affinity Fc receptor FcyRlll-aNK cells; NCT02465957), immunotherapy (NCT03228667) and orchestrated, multimodel vaccine protocols (NCT03167164).

Abraxane—paclitaxel bound to albumin shown to have increased efficacy—is in widespread use for non-small cell lung cancer (NSCLC), breast cancer and pancreatic cancer; and is being studied in other cancers.17–19 Recently, combined use of Abraxane with anti-PD-L1 therapies such as atezolizumab has achieved notable results, including prolonged progression-free survival among patients with metastatic triple-negative breast cancer (mTNBC)20 and similar findings for NSCLC have been reported.21 In addition to additive effects of combined therapy, it has also been described that the release of tumor cell-associated antigens (TAAs) by low-dose or moderate-dose Abraxane can work synergistically with immunotherapy to elicit a vaccine-like antitumor response22 and, furthermore, that taxanes such as Abraxane can act as lipopolysaccharide mimetics and activate macrophages to direct tumor cell elimination.23

We present here a case report on a 71-year-old man diagnosed with a history of gastroesophageal junction poorly differentiated carcinoma histologically appearing as small cell treated (without resection) initially with carboplatin/etoposide/XRT followed by four more cycles of carboplatin/etoposide (figure 1) ending February 2015. He achieved a mixed response, with residual disease resected from the abdominal wall and new pathology consistent with MCC (table 1). Treatment postresection consisted of 3 months of carboplatin/etoposide resulting in stable disease for approximately 20 months. On July 2016, the patient underwent abdominal surgery and wide excision of the MCC. Surgical margins were negative.

By April 2018, progressive disease was seen. On progression, a core needle biopsy (CNB) of the progressed tumor showed stage IV metastatic MCC (figure 1, January 2018 CT) and in May 2018 avelumab was initiated. After two courses of avelumab, the patient experienced acute diverticulitis. Imaging at that time showed response of the para-aortic lesion (figure 1, June 2018 CT) but not the other tumor masses. Avelumab was discontinued and symptoms resolved after a course of levofloxacin and metronidazole. Avelumab was restarted and, because CT imaging did not show a satisfactory response, after one cycle N-803 was added. An initial CT performed approximately 2 months after combined avelumab/N-803 therapy suggested possible bone metastasis and increasing activity of the target lesion, therefore, Abraxane (100 mg/M²; at days 1, 8 and 15 every 28 days) was added to further stimulate the immune response to the tumor(s). One month later, CT showed a decrease in size of the abdominal mass and, with continued avelumab/N-803/Abraxane treatment, near resolution of the mass was seen within 3 months and complete response (CR) at 5 months; continued CR for the para-aortic mass at that time is shown in figure 1, September 2019 CT. Abraxane was discontinued after the first CR on CT, the patient continues on avelumab/N-803 treatment and has maintained a CR for more than 12 months at the time of this report.

Advanced, metastatic MCC has been historically very difficult to treat, and immune checkpoint refractory patients have almost no viable therapeutic options. Our case of a CR with avelumab, N-803 and Abraxane after initial checkpoint inhibitor failure is unique because of the clinical result and the absence of conventional immunotherapy response-related biomarkers. Molecular analysis revealed features consistent with average immune cell infiltration, low TMB (although just above the cut-off for TMB of 2.0 for efficacy as described in Georges et al,27 MSS and negative status for both PD-L1 and CTLA-4; yet the patient still achieved a CR suggesting the mechanisms by which N-804 and Abraxane work in concert with avelumab to amplify the antitumor response were critical to effective therapy.

Further, as described in Knepper et al, ~22% of MCC do not have either the UV signature or MCPyV expression—as exemplified by the CNB here—and receive less benefit from checkpoint monotherapy than UV-driven MCC.2 This also points to the rationale for use of combined therapy here.

As illustrated in figure 4 and based on the known immunobiologies of the agents used, we propose the mechanism of synergy for avelumab, Abraxane, and N-803 is through release of TAAs by Abraxane cytotoxicity that attract a response from T cells freed from checkpoint suppression by avelumab. Other anti-PD-L1 therapies have shown greater efficacy when combined with Abraxane, for example, atezolizumab,20 which is now approved for TNBC; and pembrolizumab plus Abraxane (or paclitaxel plus carboplatin) for NSCLC.28 Here, this synergy was enhanced by N-803-mediated stimulation of T effector cells,10 suppression of myeloid-derived suppressor cells and thus T regulatory cells, T cell-independent cytotoxicity via NK cell upregulation and possibly PD-L1 upregulation. Further elucidation of the exact mechanism of efficacy for this therapeutic combination awaits a carefully designed clinical trial, given that for this individual patient there was no longitudinal collection of blood and tumor samples before and after each treatment that could undergo analyzes for immune correlates of response; such collection is not part of standard of care. Nonetheless, this case study suggests a promising new treatment modality for similar patients.