Adjuvant Multipeptide Vaccine Combination Prolongs Survival in Melanoma

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Adjuvant treatment with a CD8-positive T cell-targeted multipeptide vaccine (12MP) in combination with a CD4-positive T cell-directed 6 melanoma-specific helper peptides (6MHP) vaccine led to prolonged survival vs 12MP plus a nonspecific helper peptide vaccine from tetanus toxoid (tet) in patients with stage IIB to IV melanoma, according to findings from a post-hoc analysis. The post-hoc analysis of a phase 2 clinical trial (NCT00118274) published in Nature Communications also showed that benefit appeared confined to male patients.¹

At a median follow-up of 8.6 years, the median overall survival (OS) interval was not reached among patients who received 12MP plus 6MHP (n = 85) compared with 12.9 years for patients treated with 12MP plus tet (n = 82). Additionally, at 2.5 years post-enrollment, the estimates for OS favored the 6MHP arm over the tet arm (HR 0.65; 95% CI; 0.40-1.05, P = .08). The estimated 5-, 10-, and 15-year OS rates in the 6MHP arm were 74% (standard error [SE] ± 5%), 68% (SE ± 5%), and 61% (SE ± 6%), respectively; these respective rates were 68% (SE ± 5%), 56% (SE ± 6%), and 45% (SE ± 7%) in the tet arm.

“OS estimates for the 2 vaccine regimens were similar early, then they separated progressively, favoring the 12MP plus 6MHP vaccine regimen,” Emily Ninmer, MD, a surgery resident at the University of Virginia Comprehensive Cancer Center in Charlottesville, and coauthors wrote. “After 8 years, the OS estimates for 12MP plus 6MHP participants exceeded the upper bound of the 95% CI for the 12MP plus tet participants, evidence that the melanoma-cognate peptides [6MHP] significantly improved long-term OS. Interestingly, the benefit of adding 6MHP was experienced disproportionately by males.”

The multicenter, open-label trial enrolled patients with stage IIB to IV cutaneous, mucosal, or primary resected melanoma. Eligible patients also needed to have at least 2 intact and/or inguinal lymph node basins, be ineligible for or refused interferon, and they could not have ocular melanoma. Patients were required to be HLA-A1, -A2, or -A3 positive and HLA-DR1, -DR4, -DR11, -DR13, or -DR15 positive. Brain metastases were permitted if patients had no more than 3 total, each metastasis was 2 cm or less in diameter at the time of study entry, each metastasis was surgically removed or treated with stereotactic radiosurgery, and there was no evidence of brain metastasis progression following the most recent therapy.²

Patients were randomly assigned 1:1:1:1 to receive 12MP plus tet (arm A; n = 41), 12MP plus tet and cyclophosphamide (arm B; n = 41), 12MP plus 6MHP (arm C; n = 42), or 12MP plus 6MHP and cyclophosphamide (arm D; n = 43). Vaccines were given at weeks 0, 1, 2, 4, 5, 6, 12, 26, 39, and 52, and cyclophosphamide was administered at a dose of 300 mg/m² 5 days before the first vaccine dose. In the post-hoc survival analysis, arms A and B were combined to make up the 12MP plus tet group and arms C and D constituted the 12MP plus 6MHP group.

The primary end points were safety and CD8 T cell response to 12MP. Stratification occurred based on institution and class I major histocompatibility complex status.^1,2

At baseline, most patients in the 12MP plus tet (65%) and 12MP plus 6MHP (69%) arms were men and the median age was 59.7 years (range, 28.8-81.7) compared with 56.7 years (range, 21.4-77.3), respectively. Most patients in both groups had stage IIIB to D disease (54% vs 53%), an ECOG performance status of 0 (89% vs 92%), and lactate dehydrogenase less than the upper limit of normal (95% vs 98%). Fifty-six percent of patients in the tet group had recurrent disease compared with 45% in the 6MHP group.¹

Findings from a landmark analysis for OS at 2.5 years by vaccine regimen indicated a superior OS with the 6MHP vaccination (HR 0.52; 95% CI, 0.27-0.97, P = .04). Additionally, the median recurrence-free survival (RFS) in the 6MHP arm was 13.3 years vs 2.7 years in the tet arm (HR 0.77; 95% CI, 0.51-1.18, P > .22).

Notably, Kaplan–Meier estimates from a subgroup analysis showed an improved trend for OS in the 12MP plus 6MHP arm among male patients (n = 59; P = .08) but not among females (n = 26). Similarly, there was a trend favoring 6MHP in male patients in terms of RFS (HR 0.59; 95% CI, 0.34-1.02; P = .06) but not in females (HR 1.29; 95% CI, 0.67-2.49). Across the 4 total study arms, the greatest difference regarding OS was between arms A and D in favor of arm D (HR 0.56; 95% CI, 0.28-1.11); arm D was also favored over arm A in terms of RFS (HR 0.61; 95% CI, 0.33-1.10).

“This phase 2 trial was not powered for comparison of OS or RFS; so, even a promising trend for enhanced OS or RFS between the 2 vaccine regimens is at least hypothesis-generating and could justify a future definitive trial powered to test clinical benefit,” study authors wrote in conclusion. “Benefit is most evident in earlier stage patients and appears confined to males. Benefit of cyclophosphamide pretreatment is not observed in the primary comparison, but evaluation across all 4 arms, especially in males, leaves open the possibility that cyclophosphamide pretreatment may be helpful when combined with cognate T cell help. The results support design of future trials powered to evaluate long-term clinical outcomes with 12MP plus 6MHP vaccination plus PD-1 blockade vs PD-1 blockade alone, in the adjuvant setting, stratified by sex, particularly in a trial that would use a biomarker to identify high-risk patients.”

References

1. Ninmer EK, Zhu H, Chianese-Bullock KA, et al. Multipeptide vaccines for melanoma in the adjuvant setting: long-term survival outcomes and post-hoc analysis of a randomized phase II trial. Nat Commun. 2024;15:2570. doi:10.1038/s41467-024-46877-6
2. Vaccine therapy with or without cyclophosphamide in treating patients who have undergone surgery for stage II, stage III, or stage IV melanoma. ClinicalTrials.gov. Updated April 20, 2021. Accessed April 30, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT00118274