A prospective phase II clinical trial has demonstrated promising efficacy for neoadjuvant treatment with the combination of intratumoral vidutolimod and systemic nivolumab in patients with high-risk resectable melanoma. The single-arm study, conducted at the University of Pittsburgh Medical Center Hillman Cancer Center, found that the combination therapy produced a major pathologic response (MPR) rate of 55% and was associated with activation of both innate and adaptive anti-tumor immune responses. The results were published on October 31, 2024 in Cancer Cell.
The trial was funded by Checkmate Pharmaceuticals (now owned by Regeneron Pharmaceuticals) and aimed to evaluate the safety and efficacy of combining the toll-like receptor 9 (TLR9) agonist vidutolimod with the PD-1 inhibitor nivolumab in the neoadjuvant setting for stage III melanoma. Vidutolimod is a virus-like particle containing a TLR9 agonist that is designed to activate plasmacytoid dendritic cells and stimulate innate anti-tumor immunity when injected intratumorally.
The study enrolled 34 patients with clinical stage III melanoma who had at least one injectable and resectable lesion. Patients received three doses of intravenous nivolumab (240 mg every 2 weeks) along with seven weekly doses of intratumoral vidutolimod (5 mg subcutaneous for week 1, then 10 mg intratumoral for weeks 2-7) prior to surgery. The primary endpoint was MPR, defined as ≤10% residual viable tumor in the surgical specimen.
Of the 31 patients evaluable for efficacy, 17 (55%) achieved an MPR, including 14 (45%) who had a pathologic complete response. The objective response rate by RECIST criteria was 45%. With a median follow-up of 26.5 months, the 1-year and 2-year recurrence-free survival rates for patients achieving an MPR were 94% and 88%, respectively. Only 2 of 17 MPR patients (12%) experienced disease recurrence, compared to 7 of 13 non-MPR patients (54%).
The combination therapy demonstrated a manageable safety profile, with no grade 4-5 treatment-related adverse events reported. Eight patients experienced grade 3 treatment-related adverse events, most commonly hypertension. One patient developed grade 3 immune-related colitis that resolved with steroid treatment.
Correlative studies provided insights into the immunological mechanisms of action. Pathologic analysis found that MPR was associated with increased tumor-infiltrating CD8+ T cells, formation of tertiary lymphoid structures, and extensive necrosis and melanophagocytosis in the regression bed. Gene expression profiling revealed that response was linked to signatures of myeloid cells, plasmacytoid dendritic cells, CD8+ T cells, and T follicular helper cells in the tumor microenvironment.
Intriguingly, analysis of the gut microbiome found that MPR was associated with enrichment of certain Gram-negative bacteria, including members of the Bacteroidaceae and Enterobacteriaceae families. This microbiome signature differed from that previously reported to correlate with response to PD-1 blockade alone, suggesting the TLR9 agonist may alter the microbial determinants of immunotherapy efficacy.
The authors concluded that neoadjuvant vidutolimod plus nivolumab stimulates broad anti-tumor immune responses involving both innate and adaptive immunity. They noted the MPR rate of 55% compares favorably to historical data with neoadjuvant PD-1 blockade alone (19-25% MPR rates) and is similar to combination PD-1/CTLA-4 blockade (43-57% pathologic complete response rates).
Limitations of the study include its single-arm design and relatively small sample size. The authors acknowledged that the promising efficacy results will need to be validated in larger randomized controlled trials. Additionally, the study was conducted at a single academic center, potentially limiting generalizability.
Nevertheless, the findings have potentially important clinical implications. If confirmed in phase III studies, the vidutolimod/nivolumab combination could provide a new neoadjuvant treatment option for high-risk melanoma that matches the efficacy of ipilimumab/nivolumab but with a more favorable toxicity profile. The 55% MPR rate and encouraging survival data suggest the regimen may improve outcomes compared to adjuvant therapy alone.
The correlative analyses also provide new insights that could inform patient selection and future combination strategies. The identified myeloid and microbiome signatures associated with response may serve as predictive biomarkers if validated. Additionally, the broad immune activation observed, including effects on plasmacytoid dendritic cells and tertiary lymphoid structure formation, provides rationale for combining TLR9 agonists with other immunotherapies beyond PD-1 blockade.
In an accompanying editorial, experts not involved with the study called the results "practice-changing" and stated the vidutolimod/nivolumab combination "has the potential to become a new standard of care in the neoadjuvant setting for resectable stage III melanoma." They emphasized the need for randomized phase III trials comparing the regimen to current standards like ipilimumab/nivolumab and for studies evaluating the approach in other tumor types.
Several ongoing clinical trials are now evaluating vidutolimod-based combinations in melanoma and other cancers. A phase III study comparing neoadjuvant vidutolimod/nivolumab to ipilimumab/nivolumab in stage III melanoma is expected to launch in 2025. The results of these studies will help determine whether this novel immunotherapy combination can improve outcomes for patients with high-risk resectable cancers.
References
Davar D, Morrison RM, Dzutsev AK, et al. Neoadjuvant vidutolimod and nivolumab in high-risk resectable melanoma: A prospective phase II trial. Cancer Cell. 2024;42(11):1898-1918.e12. doi:10.1016/j.ccell.2024.10.007
