Updated results from the randomized phase II iNATURE trial, presented by FengMing P. Kong at ESMO 2026 , showed that combining a personalized neoantigen peptide vaccine with precision critical-lesion radiotherapy significantly improved progression-free survival in patients with heavily pretreated advanced solid tumors.
Median progression-free survival increased from 3.1 months with placebo plus radiotherapy to 10.3 months with the personalized vaccine plus radiotherapy, representing an approximately seven-month improvement.
The findings suggest that combining individualized cancer vaccines with targeted radiotherapy may offer a promising treatment strategy for patients with advanced cancers that have progressed despite multiple lines of systemic therapy.
Background
Personalized neoantigen vaccines are designed to stimulate immune responses against tumor-specific mutations identified through genomic sequencing.
Although these vaccines have demonstrated encouraging activity in earlier disease settings, their effectiveness in advanced and treatment-resistant solid tumors remains limited.
Radiotherapy may enhance antitumor immune responses by promoting tumor antigen release and altering the tumor microenvironment. However, its potential to improve the effectiveness of personalized cancer vaccines requires further clinical investigation.
The iNATURE trial evaluated whether combining a personalized neoantigen peptide vaccine (PPVax) with critical-lesion immuno-preserving radiotherapy (CLERT) could improve outcomes in patients with refractory metastatic solid tumors.
Study Design and Patient Population
The iNATURE study (GCOG0028; NCT06314087) was a randomized, placebo-controlled phase II trial involving patients with metastatic solid tumors who had experienced disease progression after at least one previous line of treatment.
Tumor genomic profiling was performed to identify potentially immunogenic mutations. Candidate neoantigens were assessed using sequencing-based methods and three artificial intelligence algorithms.
Individualized peptide vaccines, designated BXP-001, were then manufactured based on each patient’s tumor-specific neoantigens.
Patients were randomized 1:1 to receive either:
- Personalized neoantigen peptide vaccine plus CLERT.
- Placebo plus CLERT.
All patients received stereotactically planned radiotherapy targeting selected critical tumor lesions.
The vaccine regimen consisted of five priming doses during the first month, followed by four monthly booster doses.
The study assessed progression-free survival (PFS), neoantigen-specific immune responses, treatment-related adverse events, and patient-reported quality of life.
Of 114 patients screened for tumor genomic mutations, 106 had identifiable neoantigens. Forty patients met eligibility criteria and provided written consent, and 35 were eventually randomized.
The treatment groups included 16 patients receiving PPVax plus CLERT and 19 receiving placebo plus CLERT.
Most participants had lung cancer:
- Lung cancer: 26 patients (74.3%).
- Colorectal cancer: 4 patients (11.4%).
- Other solid tumors: 5 patients (14.3%).
Patients had received a median of three previous lines of systemic therapy.
Progression-Free Survival Results
The addition of personalized neoantigen vaccination to precision radiotherapy was associated with a statistically significant improvement in progression-free survival.
Median PFS was 10.3 months with PPVax plus CLERT compared with 3.1 months with placebo plus CLERT (P=0.0045). The hazard ratio for progression or death was 0.29 (95% CI, 0.12–0.71; P=0.007), corresponding to an estimated 71% relative reduction in the hazard of progression or death.
The median PFS difference between groups was approximately 7.2 months.
No statistically significant variation in the treatment effect across cancer types was reported (P=0.651), although the small number of patients in each tumor subgroup limits interpretation. These findings provide an encouraging signal that personalized neoantigen vaccination may enhance disease control when combined with precision radiotherapy.
Immune Responses and Tumor Shrinkage
The study also examined whether individualized vaccines could generate measurable immune responses against the selected neoantigens.
Among evaluable patients receiving PPVax:
- 83.3% developed neoantigen-specific T-cell responses.
- 100% demonstrated antibody responses.
These findings indicate that the individualized vaccines were immunogenic in the evaluated population.
In addition, 2 of 16 patients receiving PPVax experienced more than 30% shrinkage of liver or mediastinal metastases.
Although the number of patients with substantial tumor shrinkage was small, the findings provide preliminary evidence of antitumor activity alongside the observed immune responses.
Safety and Quality of Life
The combination of personalized vaccination and precision radiotherapy demonstrated a favorable vaccine-related safety profile in this small trial.
No grade 3 or higher adverse events attributed to PPVax were reported.
Patient-reported quality-of-life scores did not change significantly in either treatment group during the study.
These results suggest that the personalized vaccine could be incorporated into the treatment strategy without a substantial additional vaccine-related toxicity burden, although larger studies are needed to characterize safety more fully.
Clinical Implications
The iNATURE results highlight the potential of integrating personalized immunotherapy with precision radiotherapy in advanced solid tumors. The substantial difference in median progression-free survival is particularly notable because participants had previously received a median of three lines of systemic therapy. The study also provides evidence that individualized neoantigen peptide vaccines can generate both cellular and antibody immune responses in patients with refractory metastatic cancer.
However, several important limitations should be considered.
Only 35 patients were randomized, and the study included a heterogeneous population of solid tumors, predominantly lung cancer.
The findings therefore represent an early efficacy signal rather than definitive evidence supporting routine clinical use.
Because both treatment groups received CLERT, the study primarily evaluated the additional benefit of personalized vaccination rather than the independent contribution of radiotherapy or the existence of a vaccine–radiotherapy synergy.
A larger multicenter validation study is underway to further evaluate the efficacy and safety of this treatment approach.
Conclusion
The randomized phase II iNATURE trial demonstrated significantly longer progression-free survival with personalized neoantigen peptide vaccination plus precision critical-lesion radiotherapy compared with placebo plus radiotherapy in patients with heavily pretreated advanced solid tumors.
Median PFS improved from 3.1 to 10.3 months, with measurable neoantigen-specific immune responses and no reported grade 3 or higher vaccine-related adverse events. Although the findings are encouraging, confirmation in larger randomized trials is necessary before this personalized treatment approach can be incorporated into routine oncology practice.
