KEYVIBE-010: Adding Vibostolimab to Pembrolizumab Does Not Improve Outcomes in Resected High-Risk Melanoma

Why This Study Matters

Adjuvant therapy with PD-1 inhibitors — pembrolizumab or nivolumab — is now a standard of care for patients with resected stage IIB to IV melanoma. These agents have demonstrated significant improvements in recurrence-free survival and distant metastasis-free survival. However, overall survival benefit with these agents remains inconclusive, pending the maturation of data from pivotal trials including KEYNOTE-716 and KEYNOTE-054. There is a clinical need to improve on current adjuvant options.

TIGIT (T cell immunoreceptor with immunoglobulin and ITIM domains) is an inhibitory checkpoint receptor expressed on effector CD4 and CD8 T cells and natural killer cells. TIGIT competes with the stimulatory CD226 receptor to bind its ligands CD155 and CD112, thereby attenuating the immune response and inhibiting host T-cell activation and proliferation. Vibostolimab is a humanised IgG1 anti-TIGIT antibody that blocks TIGIT from interacting with CD112 and CD155 and engages Fcγ receptors on myeloid cells. The rationale for combining vibostolimab with pembrolizumab was a mechanistic one: dual PD-1 and TIGIT blockade could synergistically reactivate antitumour immunity.

KEYVIBE-010 was designed to test whether coformulating vibostolimab with pembrolizumab as adjuvant therapy could improve recurrence-free survival beyond what pembrolizumab alone delivers in this high-risk population.

Study Design

KEYVIBE-010 was a randomised, double-blind, phase 3 study conducted at 205 global sites (hospitals and cancer centres). Eligible participants were aged 12 years or older with surgically resected, histologically or pathologically confirmed stage IIB, IIC, III, or IV cutaneous melanoma per the American Joint Committee on Cancer Staging Manual 2017 (8th edition), with no evidence of metastatic disease after resection and adequate organ function.

Participants were randomly assigned (1:1) to receive vibostolimab 200 mg coformulated with pembrolizumab 200 mg or pembrolizumab 200 mg alone intravenously every 3 weeks. Treatment continued for up to 17 cycles or until recurrence or disease progression, unacceptable toxicity, prolonged interruption of treatment, or withdrawal of consent. Randomisation was stratified by risk-based staging (IIB–IIIB vs IIIC–IV) and geographical region (Asia vs rest of world).

Patient Population

Between January 19, 2023, and March 6, 2024, 1,810 participants were screened, of whom 1,402 met eligibility criteria. The median age was 61.0 years (IQR 51.0–70.0). Of 1,402 participants, 829 (59%) were male and 573 (41%) were female. The majority — 1,107 (79%) — were White, 273 (19%) were Asian, and 22 (2%) were of other race or race was missing. In terms of disease stage, 847 (60%) had stage IIB–IIIB disease and 552 (39%) had stage IIIC–IV disease. ECOG performance status was 0 in 1,175 (84%) participants.

Primary Endpoint: Recurrence-Free Survival

The primary endpoint was recurrence-free survival, defined as the time from randomisation to any recurrence (local, locoregional, regional, or distant) assessed per RECIST, or death from any cause, whichever occurred first. The protocol-prespecified first interim analysis was an event-driven nonbinding futility analysis planned for when 111 events had occurred (futility bar of observed HR 0.95).

The median recurrence-free survival was not reached in either group (HR 1.25; 95% CI 0.9–1.8). The 3-month recurrence-free survival rates were 91% in both treatment groups. By 6 months, the curves had separated — but in the wrong direction, numerically favouring the pembrolizumab monotherapy arm. The external data monitoring committee reviewed the results after 119 events and determined that the primary endpoint of recurrence-free survival had met the prespecified futility criterion. The study was unmasked, and participants receiving vibostolimab–pembrolizumab were offered the option of switching to pembrolizumab monotherapy.

Recurrence-Free Survival Across Subgroups

Vibostolimab–pembrolizumab did not provide a recurrence-free survival benefit over pembrolizumab alone across any prespecified subgroups. The hazard ratio point estimates consistently trended at or above 1.0 across all analysed subgroups.

Safety Profile

Safety was assessed in all 1,398 participants who received at least one dose of study treatment (698 in the vibostolimab–pembrolizumab group and 700 in the pembrolizumab alone group).

All-cause adverse events occurred in 574 (82%) of 698 participants in the vibostolimab–pembrolizumab group and 558 (80%) of 700 in the pembrolizumab alone group. Grade 3 or higher adverse events occurred in 153 (22%) and 76 (11%) participants in the combination and monotherapy groups, respectively.

Treatment-related adverse events occurred in 517 (74%) of 698 participants in the vibostolimab–pembrolizumab group, compared with 462 (66%) of 700 in the pembrolizumab alone group. The most common treatment-related adverse events (≥15%) in the combination arm were pruritus (166 [24%]), rash (162 [23%]), and fatigue (111 [16%]). In the pembrolizumab alone group, the most common treatment-related adverse event (≥15%) was fatigue (116 [17%]).

Grade 3–5 treatment-related adverse events occurred in 111 (16%) of 698 participants in the vibostolimab–pembrolizumab group, with adrenal insufficiency (13 [2%]), hepatitis (11 [2%]), rash (9 [1%]), maculopapular rash (7 [1%]), pruritus (6 [1%]), colitis (4 [1%]), hypophysitis (4 [1%]), and type 1 diabetes (4 [1%]) being the only events to occur in ≥1% of participants. Grade 3–5 treatment-related adverse events occurred in 48 (7%) of 700 in the pembrolizumab alone group.

Treatment-related serious adverse events occurred in 74 (11%) participants in the combination group and 30 (4%) in the monotherapy group. Treatment-related adverse events led to death in two (<1%) participants in the vibostolimab–pembrolizumab group (myasthenia gravis [n=1] and myocarditis [n=1]) and one (<1%) participant in the pembrolizumab alone group (myositis).

Immune-mediated adverse events and infusion reactions occurred in 212 (30%) of 698 participants in the vibostolimab–pembrolizumab group and 168 (24%) of 700 in the pembrolizumab alone group. The most common (≥5%) in both groups were hyperthyroidism (88 [13%] and 81 [12%], respectively) and hypothyroidism (69 [10%] and 65 [9%], respectively).

Interpretation and Broader Context

The first interim analysis of KEYVIBE-010 clearly showed that vibostolimab coformulated with pembrolizumab did not provide additional clinical benefit versus pembrolizumab alone as adjuvant therapy in participants with resected stage IIB–IV melanoma. The recurrence-free survival hazard ratio was 1.25, numerically favouring the pembrolizumab monotherapy arm. The external data monitoring committee stopped the trial after the prespecified futility criterion was met.

These results add to a body of evidence from clinical trials suggesting that anti-TIGIT antibodies might have limited added efficacy when combined with anti-PD-1 or anti-PD-L1 antibodies. Several other phase 3 trials evaluating anti-TIGIT agents — including the SKYSCRAPER-01 and SKYSCRAPER-02 trials of tiragolumab plus atezolizumab — have failed to show additional benefit in non-small cell lung cancer or extensive-stage small-cell lung cancer.

The safety profile of the vibostolimab–pembrolizumab combination was consistent with prior studies (KEYVIBE-001). A higher rate of treatment-related adverse events, including grade 3 or higher events (16% vs 7%), was observed in the combination group compared with pembrolizumab alone. Immune-mediated adverse events and infusion reactions were also higher (30% vs 24%), which is not unexpected given the combination of two immunotherapies with different mechanisms of action.

What This Study Does Not Show

The interim analysis that ended KEYVIBE-010 was conducted at a median study follow-up of 4.2 months (IQR 1.9–6.7), with recurrence-free survival events in only 119 of 1,402 participants (8%). Median recurrence-free survival had not been reached in either group. Recurrences in resected melanoma accrue over years, so these estimates are immature — the curve separation described above rests on a small fraction of the events the trial was designed to observe, and cannot be read as a mature description of either regimen’s longer-term performance.

Futility is not the same as harm. The hazard ratio of 1.25 carried a 95% confidence interval of 0.9–1.8, which crosses 1.0. The trial did not establish that adding vibostolimab makes outcomes worse; it established that the combination was unlikely to clear the prespecified bar for benefit if the study continued. The point estimate favours monotherapy, but the interval remains compatible with no difference between the groups.

No overall survival comparison is reported, and stopping at the first interim analysis means none is likely to mature. Participants were enrolled without selection for TIGIT expression, and the trial was not designed to test whether a biomarker-defined subgroup might respond differently — though no prespecified subgroup showed benefit, with hazard ratios at or above 1.0 throughout. The safety comparison is drawn from the same short follow-up window. The study was funded by Merck Sharp & Dohme, which manufactures both agents.

“Pembrolizumab monotherapy remains a standard of care for resected high-risk melanoma. There remains an opportunity to further optimise treatment in this adjuvant setting.”
— KEYVIBE-010 Study Investigators

Following these results, the clinical development of vibostolimab has been discontinued. PD-1 inhibitors remain the standard of care for patients with high-risk resected melanoma, and the search continues for novel immunotherapy combinations that can meaningfully improve on current adjuvant options in this setting.