Individualized neoantigen therapy intismeran autogene (intismeran) plus pembrolizumab (pembro) in resected melanoma: 5-year update of the KEYNOTE-942 study.

9500 Background: Intismeran is an mRNA-based individualized neoantigen therapy designed to increase endogenous neoantigen-specific antitumor T-cell responses. The phase 2b KEYNOTE-942 study of high-risk resected melanoma showed clinically meaningful improvements in recurrence-free survival (RFS) and distant metastasis–free survival (DMFS) with intismeran + pembro vs pembro alone at primary analysis. Intismeran + pembro had a manageable safety profile without potentiation of immune-related AEs vs pembro alone. Clinical benefits of intismeran + pembro were sustained at 3 y, with a 49% risk reduction of RFS and 62% risk reduction of DMFS. Intismeran + pembro also induced greater novel T-cell clonal expansion vs pembro, which was positively associated with RFS for intismeran + pembro but not pembro alone. We report results from KEYNOTE-942 after 5 y of planned follow-up. Methods: Eligible participants (pts; aged ≥18 y) with resected stage IIIB–IV cutaneous melanoma were randomized 2:1 to receive 9 doses of intismeran 1 mg IM Q3W + 18 doses of pembro 200 mg IV Q3W or 18 doses of pembro 200 mg Q3W alone. Primary endpoint was RFS; secondary endpoints included DMFS and safety. Exploratory endpoints included OS. No alpha was assigned to this analysis. Results: From Jul 2019 to Sep 2021,157 pts were randomized to intismeran + pembro (n=107) or pembro (n=50). With an additional 2 y of follow-up (data cutoff, Dec 15, 2025; median planned follow-up, 60.3 [range, 50.5–76.4] mo) after the 3-y analysis, minimal new events occurred. RFS risk reduction for intismeran + pembro vs pembro alone was 49% (HR, 0.51; 95% CI, 0.29–0.89), with landmark 5-y RFS rates of 68.8% (95% CI, 56.3%–78.3%) for intismeran + pembro vs 49.1% (95% CI, 33.3%–63.0%) for pembro alone. DMFS risk reduction was 59% (HR, 0.41; 95% CI, 0.20–0.84). In the intismeran + pembro arm, 7 pts (6.5%) died (disease progression, n=4) vs 7 pts (14.0%) in the pembro arm (disease progression, n=6). There was a trend for improved OS (HR, 0.47; 95% CI, 0.17–1.35); 5-y rate was 92.2% (95% CI, 84.2%–96.3%) for intismeran + pembro vs 71.3% (95% CI, 35.4%–89.6%) for pembro alone. The safety profile of intismeran was consistent with prior analyses. Conclusions: After a median 5 y of follow-up, intismeran + pembro continued to prolong RFS and DMFS, along with a trend for improved OS vs pembro alone in pts with high-risk resected melanoma. These long-term findings show that intismeran + pembro treatment benefits were sustained and durable over time, despite all pts having completed study treatment before primary analysis (2021). As reported previously, intismeran was well tolerated, with a manageable safety profile for intismeran + pembro. Intismeran + pembro is being evaluated in a phase 3 study of high-risk resected stage II–IV melanoma (INTerpath-001; NCT05933577) and in studies of pts with other malignancies. Clinical trial information: NCT03897881 .