Phase 3 Neoantigen Win Versus Active PD-1 Faces OS Safety and Scale Test

Merck and Moderna Announce Positive Phase 3 INTerpath-001 Results for Melanoma

Merck and Moderna announced detailed positive recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) results from the Phase 3 INTerpath-001 trial. The study evaluated intismeran autogene, an mRNA-based individualized neoantigen therapy, in combination with KEYTRUDA for adjuvant treatment of completely resected stage IIB-IV melanoma. The combination significantly reduced the risk of recurrence or death by 42% (HR=0.58; p<0.001) and distant metastasis or death by 38% (HR=0.62; p=0.002) compared to KEYTRUDA alone after a median follow-up of 24.6 months. These late-breaking results will be presented at the ESMO Congress 2026 Presidential Symposium and accepted for publication in The New England Journal of Medicine, highlighting a potential foundational shift in melanoma treatment.

• Superior Efficacy in Adjuvant Melanoma: The INTerpath-001 trial demonstrated that intismeran autogene plus KEYTRUDA significantly improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in patients with high-risk resected stage IIB-IV melanoma. The combination reduced the risk of recurrence or death by 42% and distant metastasis or death by 38% compared to KEYTRUDA monotherapy, setting a new benchmark in the adjuvant setting.
• Enhanced Benefit Post-Immunization Regimen: A pre-specified sensitivity analysis showed a more pronounced benefit after the initial six-month intismeran immunization. Following this period, the combination reduced the risk of recurrence or death by 58% (HR=0.42) and distant metastasis or death by 50% (HR=0.50). This suggests a sustained and growing anti-tumor immune response from the individualized neoantigen therapy.
• Consistent Safety and Broad Clinical Program: The safety profile of intismeran plus KEYTRUDA was consistent with prior studies, with no new safety signals observed. These pivotal Phase 3 results, which are being shared at ESMO 2026 and published in The New England Journal of Medicine, are informing regulatory discussions and support the ongoing robust INTerpath clinical development program across multiple tumor types, including NSCLC.

Addressing the Unmet Need in Adjuvant High-Risk Melanoma

Despite effective adjuvant options, completely resected high-risk melanoma remains characterized by substantial relapse risk and treatment burden. Adjuvant therapy in stage III significantly lowered relapses, although the effect on survival is less evident, and survival remains unsatisfactory even with modern systemic therapy available at relapse.

• Persistent high recurrence risk and limited survival: Recurrence was observed in 170 (62.2%); 102 (45.5%) deaths in stage IIIC and 28 (57.1%) in stage IIID were reported. RFS and OS in the IIIC group were 19.7 and 36.2 months, respectively, and in IIID - 8.9 and 27.8 months, respectively. Nearly two-thirds of the relapses occurred within the first 2 years of diagnosis, and nearly one-third of all melanoma patients will experience disease recurrence.

• Treatment discontinuation driven by toxicity: Dabrafenib and trametinib discontinuation rate due to treatment-related adverse events (TRAEs) of any grade was 9%. The median time to treatment discontinuation was 9 months [95% confidence interval (CI), 5-11]. G3-4 TRAEs occurred in 21.5% of patients, the most common being pyrexia (3%), asthenia (3%), and diarrhoea (3%). Unscheduled hospitalisations and clinical tests occurred in 6 and 22% of patients, respectively.

• Uncertain comparative efficacy in resected stage III disease: The median RFS was not reached (95% CI not estimable [NE]) in the pembrolizumab group and was 25 months in the IFN-α-2b group, and there was no significant difference in RFS between the pembrolizumab and IFN-α-2b groups (HR = 1.20, log-rank p = 0.75). For patients with IIIC or IIID melanoma, the RFS in the pembrolizumab group was also similar to that of the IFN-α-2b group (HR = 0.80, log-rank p = 0.47). Grade 3-4 adverse events occurred in 6 (22.22%) of 27 patients in the IFN-α-2b group, compared with 2 (6.90%) patients in the pembrolizumab group, with immune-related adverse events observed in 5 (17.24%) patients in the pembrolizumab group.

INTerpath-001: Significant Recurrence-Free Survival in Melanoma

The KEYNOTE-942 study evaluated adjuvant intismeran autogene (formerly V940 or mRNA-4157) plus pembrolizumab versus pembrolizumab monotherapy in completely resected high-risk cutaneous melanoma. The study was an open-label, randomised, phase 2b trial enrolled from sites in the USA and Australia and registered at ClinicalTrials.gov, NCT03897881.

Intismeran Autogene: Pioneering Individualized Neoantigen Therapy

Messenger RNA-based individualized neoantigen therapy mRNA-4157 (V940) plus pembrolizumab has emerged as a leading novel approach for completely resected high-risk melanoma. In the open-label, randomised, phase 2b KEYNOTE-942 study in patients with completely resected high-risk cutaneous melanoma (stage IIIB-IV), 157 patients were assigned 2:1 to mRNA-4157 plus pembrolizumab (n=107) or pembrolizumab monotherapy (n=50), with mRNA-4157 administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. Recurrence-free survival was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death, 0·561 [95% CI 0·309-1·017]; two-sided p=0·053), with lower recurrence or death event rate (24 [22%] of 107 vs 20 [40%] of 50); 18-month recurrence-free survival was 79% (95% CI 69·0-85·6) versus 62% (46·9-74·3). The mRNA-4157 vaccine, which encodes up to 34 patient-specific neoantigens, is designed to induce T-cell responses and potentiate antitumor activity with pembrolizumab.

Mechanistic and longer-term follow-up data support durability of this synergy in the adjuvant setting. In the first-in-human, phase 1 KEYNOTE-603 study (NCT03313778), mRNA-4157 alone induced consistent de novo and strengthened preexisting T-cell responses to targeted neoantigens, while combination with 200-mg pembrolizumab produced sustained mRNA-4157-induced neoantigen-specific T-cell responses and expansion of cytotoxic CD8 and CD4 T cells. The ASCO 3-year update reported 2.5-year RFS 74.8% vs. 55.6% and sustained distant metastasis-free survival benefit in resected high-risk melanoma, consistent with relapse-free survival of 76.6% vs 60% (hazard ratio, 0.56 [95% CI, 0.31-1.02]; P = .05) described for resected high-risk stage IIIB to IV cutaneous melanoma. Grade ≥3 treatment-related adverse events occurred in 25% of patients in the combination group and 18% of patients in the monotherapy group, with no mRNA-4157-related grade 4-5 events, and immune-mediated adverse event frequency was similar for the combination (37 [36%]) and monotherapy (18 [36%]) groups.

Beyond neoantigen platforms, combination adjuvant approaches are now investigating anti-programmed death-1 (PD1) with lymphocyte activation gene 3 (LAG3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and individualized neoantigen therapies for resected stage IIB through IV disease. The phase 3, double-blind RELATIVITY-098 trial compared adjuvant nivolumab 480 mg plus relatlimab 160 mg (n = 547) to nivolumab 480 mg (n = 546) intravenously every 4 weeks for ≤1 year after complete resection of stage III/IV melanoma, with no difference in recurrence-free survival for nivolumab plus relatlimab versus nivolumab (hazard ratio = 1.01; 95% confidence interval: 0.83-1.22; P = 0.928). Translational data showed lower circulating LAG-3 T cells in the adjuvant setting (RELATIVITY-098) versus advanced melanoma (RELATIVITY-047). The field awaits the pivotal Phase III clinical trial of V940-001 (NCT05933577), whose timeline has been extended to 2029.

Beyond Melanoma: The Expanding INTerpath Clinical Program

The INTerpath program extends evaluation of intismeran autogene plus pembrolizumab beyond resected melanoma into non-small cell lung cancer (NSCLC). Two ongoing randomized trials, INTerpath-002 and INTerpath-009, evaluate the addition of intismeran to adjuvant pembrolizumab-based therapy in stage II-IIIB (N2) NSCLC.

• INTerpath-002 population: Completely resected, margin-negative, stage II-IIIB (N2) NSCLC (American Joint Committee on Cancer staging manual, eighth edition) in participants who have received 1 to 4 cycles of adjuvant platinum-based chemotherapy.

• INTerpath-009 population: Resectable stage II-IIIB (N2) NSCLC in participants who have received ≤4 cycles of neoadjuvant pembrolizumab plus chemotherapy every 3 weeks, with eligibility for randomized treatment limited to tumors that do not achieve a pathologic complete response, per pathologic examination of the resected tumor specimen, and have R0-R1 resection.

• Intervention model for both trials: Randomized, double-blind, phase 3 trials with participants randomized 1:1 to receive pembrolizumab intravenously every 6 weeks plus either intismeran intramuscularly every 3 weeks or placebo, with primary endpoint of disease-free survival per investigator.

• Investigational agent definition: Intismeran autogene (intismeran; formerly V940, mRNA-4157), an mRNA-based individualized neoantigen therapy (INT) encoding ≤34 neoantigens unique to each patient's tumor, designed to promote an antitumor immune response.

Personalized mRNA Neoantigens: A New Era for Adjuvant Melanoma

The detailed positive results from the Phase 3 INTerpath-001 trial mark a significant moment for personalized oncology, particularly in the adjuvant treatment of resected stage IIB-IV melanoma. For years, immune checkpoint inhibitors like pembrolizumab have been the cornerstone of adjuvant therapy, demonstrating substantial improvements in recurrence-free and distant metastasis-free survival for high-risk patients. However, the new data, showing a 42% reduction in recurrence or death and a 38% reduction in distant metastasis or death when intismeran autogene is added to KEYTRUDA, suggests a profound leap forward.

This combination therapy leverages an individualized mRNA-based neoantigen approach, which research indicates can induce and strengthen patient-specific T-cell responses against tumor neoantigens. This mechanism is believed to enhance the anti-tumor activity of checkpoint inhibition, leading to the superior outcomes observed. The strong efficacy data, slated for presentation at a major oncology congress and publication in a top-tier medical journal, underscores the potential for this regimen to become a new standard of care, offering patients a more robust defense against recurrence.

However, the path to widespread adoption is not without its complexities. Individualized neoantigen therapies, while highly promising, inherently present significant logistical and economic hurdles. The manufacturing process, which involves creating a bespoke vaccine for each patient, can entail a considerable wait time—potentially 8-16 weeks—which could be a critical period for patients at high risk of recurrence. Furthermore, navigating the regulatory landscape for such 'n-of-1' therapeutics is a novel challenge, potentially impacting the speed and breadth of market access. While the clinical benefit is clear, the practicalities of delivery and cost-effectiveness will be crucial considerations for healthcare systems and patients alike. This development firmly places personalized mRNA vaccines at the forefront of cancer immunotherapy, but also highlights the need for innovative solutions to overcome the unique challenges of precision medicine.