Extending the Frontiers of Checkpoint Inhibition in Merkel Cell Carcinoma

Immunotherapy for patients with advanced MCC

In the treatment of patients with unresectable or metastatic Merkel cell carcinoma (MCC), immune checkpoint inhibitors (ICIs) against PD-1 and PD-L1 have completely supplanted chemotherapy due to their superior activity and tolerability. This has spurred investigations testing the reaches of ICI therapy in the adjuvant and metastatic settings. Treatment with an anti–PD-(L)1 antibody induces a response in approximately 40% to 60% of patients with metastatic MCC, according to data from 3 key studies, especially when given as first-line therapy. Approximately one-third to half of the responses are complete responses, which are very durable, with the majority of responses still ongoing at 1 year of follow-up (Table).^1-3 As in other cancer populations, the drugs are tolerable, and approximately less than 15% of patients discontinued therapy due to adverse effects.

Avelumab (Bavencio), an anti–PD-L1 antibody, was approved by the FDA for MCC in 2017 as the drug’s first indication. In the phase 2 JAVELIN Merkel 200 trial (NCT02155647), patients with chemotherapy-refractory MCC who received avelumab experienced rapid and robust responses within a brief period of days to weeks. Approximately 25% of individuals had already met the criteria for an objective response by the first on-study tumor assessment, which was performed at week 7. The overall survival (OS) rate among patients with a response at week 7 (n = 20) at 18 months was 90% (95% CI, 65.6%-97.4%) vs 26.2% (95% CI, 15.7%-37.8%) among patients who did not have a response at week 7 (n = 62). After adjustment for age, presence/absence of visceral metastases, and number of previous therapies, patients who achieved a response at any point on the study had a 95% reduced risk of death compared with patients who did not respond (HR, 0.052; 95% CI, 0.018- 0.152).⁴ These data on the interplay between response and long-term survival underscore how difficult it is to counsel newly diagnosed patients with stage IV MCC about prognosis prior to the initiation of treatment, as their response to PD-(L)1-directed therapy is the key factor in predicting long-term survival.

The FDA approval of avelumab for the treatment of patients with MCC was followed by approvals for pembrolizumab (Keytruda) in 2018 and retifanlimab- dlwr (Zynyz) in 2023. Pembrolizumab and retifanlimab are monoclonal antibodies against PD-1. MCC is the first indication for retifanlimab, and the approval was based on findings from the phase 2 POD1UM-201 study (NCT03599713) of 65 patients with MCC who had not had prior systemic therapy for advanced disease. The overall response rate (ORR) was 52% (95% CI, 40%-65%). In the safety population (n = 105), no new safety signals were identified. Retifanlimab is given at a flat dose of 500 mg intravenously (IV) every 4 weeks.⁵

Despite extensive analysis of biomarkers, such as PD-L1, tumor mutational burden, and viral status, no biomarker has been shown to be a reliable and significant predictor of response. Because responses are frequent, even among those without favorable features, pretreatment testing is not performed in standard practice prior to the initiation of therapy. Recently, the ratio of a subset of intratumoral myeloid cells (CD163+, CD14+, S100A8+) to intratumoral CD8 cells using a multiplex immunohistochemistry panel has been proposed as a biomarker of unfavorable response, but more data are necessary to determine its clinical validity.⁶

Exploring ICI Utility in the Adjuvant Setting

Currently there are no published data or guidelines to support the use of adjuvant immunotherapy in patients with MCC who have been definitively treated with surgery and/or radiation therapy. In melanoma, studies have demonstrated the efficacy and safety of ICIs in the adjuvant setting, leading to the FDA approvals of pembrolizumab and nivolumab (Opdivo) for fully resected stage IIB to III melanoma. Given that response rates to PD-(L)1 inhibitors are generally higher in studies of patients with metastatic MCC compared with patients with metastatic melanoma, and that the rates of recurrence are substantially higher in MCC, it is a worthwhile venture to test ICIs in the adjuvant setting for patients with definitively treated MCC.^7-10

The phase 2 ADMEC-O study (NCT02196961) assessed the effect of adjuvant PD-1 inhibition on disease-free survival (DFS) in patients with stage I to IV MCC who had been adequately treated by surgical resection or curative irradiation. A total of 179 patients at 20 centers in Germany and the Netherlands were randomly assigned 2:1 to receive adjuvant nivolumab 480 mg IV every 4 weeks for 1 year (n = 118) or observation (n = 61). At a median follow-up of 24.3 months (IQR, 19.2-33.4), the DFS rate at 1 year in the nivolumab group was 85% vs 77% in the observation group for an absolute risk reduction of 9% (95% CI, 2%-20%). The HR was 0.58 (95% CI, 0.30-1.12); however, the authors considered this to be an exploratory study. More than one-third of the study population had stage I or II disease, and the number of events observed was fewer than anticipated at the 12-month landmark. Another feature of the ADMEC-O study that limits the interpretation of its findings is that adjuvant radiation therapy was more common in the observation group vs the nivolumab-treated group (74% vs 50%), which may have narrowed the difference in DFS between the groups. Median OS data are immature and have not been reported to date.¹¹

Two US multisite randomized controlled studies for adjuvant therapy completed accrual within the past year. The phase 3 STAMP study (NCT03712605) is an ECOG trial in which patients were randomly assigned to adjuvant pembrolizumab 200 mg IV every 3 weeks for 1 year vs standard observation. The study enrolled its goal of 280 patients, and data have not been reported yet. The other trial, the phase 3 ADAM study (NCT03271372), randomly assigned 100 patients with stage III MCC to treatment with avelumab vs placebo in double-blind fashion. On this study, avelumab is given for a total of 2 years, including maintenance dosing every 4 months during the second year, which is a unique feature of this trial. The results from these 2 studies and the final analysis of the ADMEC-O trial are highly anticipated, as the results are potentially practice changing.^12,13

Doubling Down: Dual Checkpoint Blockade

In the metastatic setting, when anti–PD-(L)1 therapy fails to control the patient’s disease, there are very few options besides chemotherapy or a clinical trial. Given the responsiveness to monotherapy in metastatic MCC, it was hypothesized that dual checkpoint blockade including CTLA-4 inhibition, much like in melanoma, would be beneficial to patients with MCC refractory to anti–PD-1 therapy. In a multicenter retrospective study of the prospective multicenter skin cancer registry ADOREG, 14 patients with unresectable MCC who had disease refractory to avelumab were treated with ipilimumab (Yervoy) plus nivolumab as subsequent therapy (second or later line). Seven patients responded to ipilimumab plus nivolumab for an ORR of 50%. At 12 months and 24 months, the progression-free survival rates were 42.9% and 26.8%, respectively. The OS rate at 36 months was 64.3%.¹⁴

Ipilimumab plus nivolumab was further explored in a phase 2 trial (NCT03071406) using stereotactic body radiation therapy (SBRT) as an adjunct to dual ICI. All patients, including previously treated patients and ICI-naive patients, were treated with low-dose ipilimumab (1 mg/kg IV every 6 weeks) and nivolumab (240 mg IV every 2 weeks). Fifty patients with MCC were randomly assigned to receive ipilimumab plus nivolumab (n = 25) vs ipilimumab plus nivolumab in combination with SBRT (n = 25) to 1 metastatic site. The primary intervention, the SBRT, did not show any improvement in response rate. In fact, the response rate was slightly lower. In a secondary subset analysis of patients who had received prior treatment with ICI (n = 26), the response rate was 31% (95% CI, 15%-52%). On the other hand, all patients who had not received an ICI (25/25) achieved an objective response.¹⁵

This surprisingly favorable finding led to further interest in dual checkpoint blockade as a first-line treatment. Data from the phase 1/2 CheckMate 358 study (NCT02488759) were presented at the 2023 American Society of Clinical Oncology Annual Meeting. In this study, ICI-naive patients with recurrent or metastatic MCC were assigned to an arm by their treating physician in an open-label fashion, either nivolumab monotherapy or ipilimumab plus nivolumab. In the nivolumab arm (n = 25), 15 patients responded, and in the ipilimumab plus nivolumab arm (n = 43), 25 patients responded, which constituted an ORR of 60.0% (95% CI, 38.7%-78.9%) vs 58.1% (95% CI, 42.1%-73.0%), respectively. The results between the arms should not be compared directly because patients were not randomly assigned. It can be assumed that the treating physicians might have assigned patients with a heavier tumor burden or more visceral disease to the dual checkpoint arm more often than those with a limited tumor burden.¹⁶

Given the large difference in response rates between the ICI-naive subset in the SBRT study by Kim, et al and the CheckMate 358 study population, there are conflicting data about exactly how effective dual immunotherapy checkpoint combination therapy is for first-line patients with untreated MCC. Despite these differences, a plurality of ICI-naive patients in both prospective clinical trials responded to ipilimumab plus nivolumab. However, the activity against the disease must be balanced with the toxicity of the regimen, especially in the firstline setting wherein monotherapy performs well with less toxicity. In the SBRT study, 16% of patients of patients discontinued therapy due to treatment-related toxicity.¹⁵ Similarly, in the CheckMate 358 study, 25.6% of patients discontinued therapy.¹⁶ Due to toxicity concerns, ipilimumab plus nivolumab has not been widely adopted as a first-line regimen for metastatic MCC and remains an off-label treatment. However, ipilimumab plus nivolumab remains an appealing alternative to chemotherapy as a salvage regimen for patients who have progressive disease despite treatment with a PD-(L)1 inhibitor, and it is listed in the NCCN guidelines as consideration for salvage therapy.

The high rate and durability of responses to checkpoint blockade therapy in MCC led to approvals for 3 drugs based on single-arm studies in metastatic disease. High-quality clinical trial data in the adjuvant setting are being collected now and will be extremely important for the advancement of the field. In the salvage setting, additional clinical investigations are needed to define the optimal population for treatment with ipilimumab plus nivolumab, and explorations of novel immune and molecular targets are urgently needed.

Ann W. Silk, MD, MS, is codirector of the Merkel Cell Carcinoma Center of Excellence and a physician at Dana-Farber Cancer Institute as well as an assistant professor of medicine at Harvard Medical School in Boston, Massachusetts.

James A. DeCaprio, MD, is a physician at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School.

References

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