High Clinical Impact: Neoadjuvant Synergy in Merkel Cell Carcinoma
Highlights
The primary results of this investigator-initiated Phase II trial highlight three critical findings for the management of Merkel cell carcinoma (MCC):
1. A pathological complete response (pCR) rate of 57.7% was achieved with only six weeks of neoadjuvant lenvatinib and pembrolizumab.
2. The objective response rate (ORR) among radiographically evaluable patients reached 72.7%.
3. Progression-free survival (PFS) demonstrated a significant correlation with radiographic response, with a median PFS not yet reached at 20 months.
The Evolving Landscape of Merkel Cell Carcinoma
Merkel cell carcinoma (MCC) is a rare but exceptionally aggressive neuroendocrine carcinoma of the skin. Historically, patients with resectable stage II-IV disease faced high rates of recurrence and poor long-term survival when treated with surgery and radiation alone. The advent of immune checkpoint inhibitors (ICIs), specifically those targeting the programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) axis, has revolutionized the treatment of advanced and metastatic MCC. However, there remains a significant unmet medical need in the neoadjuvant setting, where systemic therapy prior to definitive surgery might improve surgical outcomes and long-term systemic control.
Traditional neoadjuvant approaches in other skin cancers, such as melanoma, have shown that achieving a pathological complete response (pCR) is a powerful predictor of long-term survival. This trial investigates whether combining the multikinase inhibitor lenvatinib with the PD-1 inhibitor pembrolizumab can maximize early tumor shrinkage and pathological clearance in MCC.
Biological Rationale: Lenvatinib and Pembrolizumab Synergy
The combination of lenvatinib and pembrolizumab is grounded in a strong mechanistic rationale. Lenvatinib is a potent inhibitor of vascular endothelial growth factor (VEGFR) receptors 1, 2, and 3, as well as fibroblast growth factor (FGFR) receptors, platelet-derived growth factor (PDGFR) receptor alpha, and the KIT and RET proto-oncogenes.
In the tumor microenvironment, VEGF-mediated signaling is known to contribute to immunosuppression by inhibiting dendritic cell maturation and promoting the infiltration of myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs). By inhibiting these pathways, lenvatinib may not only exert direct anti-angiogenic effects but also reprogram the microenvironment into an immune-supportive state, thereby enhancing the efficacy of pembrolizumab. This trial, NCT04869137, represents a critical step in translating this synergistic potential to the neoadjuvant MCC setting.
Study Design and Methodology
This single-center, phase II, open-label trial enrolled 26 patients with resectable clinical stage II-IV MCC. The patient cohort was predominantly stage III (76.9%), reflecting the high-risk nature of the population.
Intervention Protocol
The neoadjuvant phase consisted of a 6-week regimen:
– Lenvatinib: 20 mg orally daily.
– Pembrolizumab: 200 mg intravenously every 3 weeks (total of two doses).
Following the 6-week window, patients underwent local therapy (surgery). Postoperatively, patients continued to receive adjuvant pembrolizumab monotherapy for a total treatment duration of one year. The primary endpoint was the rate of pathological complete response (pCR), defined as the absence of viable tumor cells in the surgical specimen.
Key Findings: Efficacy and Pathological Outcomes
The trial met its primary objective with impressive efficacy results. In the intention-to-treat (ITT) population of 26 patients, 15 (57.7%) achieved a pCR. This high rate of pathological clearance after only six weeks of therapy is notable in the context of MCC treatment history.
Radiographic and Survival Data
Of the 22 patients who were radiographically evaluable, 16 (72.7%) achieved an objective response prior to surgery. At a median follow-up of 20.0 months, the median progression-free survival (PFS) had not been reached.
One of the most clinically relevant findings was the correlation between treatment response and survival. PFS significantly correlated with the radiographic response to neoadjuvant therapy. While pCR was numerically associated with superior PFS, this specific correlation did not reach statistical significance (p=0.22), likely due to the small sample size and the overall high survival rate in the responder group.
Surgical Feasibility
It is important to note the impact of neoadjuvant therapy on surgical planning. Two patients (7.7%) were unable to undergo the planned surgery: one due to rapid disease progression and one due to treatment-related toxicity. For the remaining patients, the short duration of neoadjuvant therapy did not appear to cause significant delays in definitive local treatment.
Safety and Tolerability
Safety is a paramount concern when combining a potent TKI with an ICI in the neoadjuvant setting, where patients are being prepared for surgery. Grade 3 treatment-related adverse events (TRAEs) were reported in 14 patients (53.8%).
Management of Adverse Events
The most common Grade 3 TRAE was hypertension, occurring in 11 patients (42.3%). This is a known effect of lenvatinib’s VEGF inhibition and was manageable with antihypertensive medications and dose modifications. Importantly, no Grade 4 or 5 TRAEs were observed, suggesting that the regimen, while intensive, is manageable within experienced oncology centers. Clinicians must remain vigilant in monitoring blood pressure and other TKI-associated toxicities like proteinuria or fatigue during the neoadjuvant window.
Expert Commentary and Clinical Implications
The pCR rate of 57.7% observed in this trial is highly encouraging. In comparison, neoadjuvant PD-1 monotherapy trials in MCC have shown pCR rates in the range of 47%. The addition of lenvatinib appears to increase the depth of response, though a randomized trial would be required to definitively prove the superiority of the combination over pembrolizumab alone.
Mechanistic Insights
The success of this combination suggests that the ‘vascular normalization’ and ‘immune priming’ effects of lenvatinib are particularly effective in MCC, a tumor type known for its high immunogenicity (often driven by Merkel cell polyomavirus or high UV mutational burden). The radiographic response’s strong correlation with PFS provides clinicians with an early surrogate to gauge long-term prognosis.
Limitations
The primary limitations include the single-center design and the relatively small sample size (n=26). Additionally, the dose of lenvatinib (20 mg) is substantial, contributing to the high rate of Grade 3 hypertension. Future studies might explore whether a lower dose or a different TKI could maintain efficacy while reducing the toxicity burden.
Summary and Future Directions
The combination of neoadjuvant lenvatinib and pembrolizumab represents a potent new strategy for patients with resectable Merkel cell carcinoma. By achieving a pCR in more than half of the patients within six weeks, this regimen may reduce surgical morbidity and significantly improve the durability of remission. These findings warrant further validation in larger, multi-center Phase III trials and potentially support the integration of dual TKI-ICI neoadjuvant therapy into standard clinical guidelines for high-risk MCC.
Funding and Registration
This study was an investigator-initiated trial supported by Merck Sharp & Dohme and Eisai. ClinicalTrials.gov Identifier: NCT04869137.
References
Brohl AS, Sondak VK, Wuthrick EJ, et al. Neoadjuvant lenvatinib plus pembrolizumab in Merkel cell carcinoma: an investigator-initiated, open-label phase II trial. J Immunother Cancer. 2026 Jan 14;14(1):e013939. doi: 10.1136/jitc-2025-013939. PMID: 41534900.
