Part 2｜Inside AMPLIFY-201 Final Analysis: What the KRAS Vaccine Is Actually Moving

Takeaway: Lymph-node–targeted amphiphile delivery achieved robust dual CD4/CD8 responses. A data-driven ~9.17× immune threshold aligned with RFS/OS gains and ctDNA negativity in the adjuvant MRD setting.

Contents

1. 1. One-Minute Summary
2. 2. Study Design & Population
3. 3. Endpoints: Immune, Molecular, Clinical
4. 4. Key Results: Threshold, ctDNA, Survival
5. 5. Response Quality & Antigen Spreading
6. 6. Safety & Implementability
7. 7. Limitations & Generalizability
8. 8. Implications for Practice & Development
9. 9. FAQ
10. 10. Outlook (Editorial View)
11. 11. Next Up

1. One-Minute Summary

• Setting: Post-resection, post-standard-therapy but MRD-positive PDAC/CRC.
• Intervention: ELI-002 2P (KRAS G12D/G12R) with amphiphile chemistry for lymph-node targeting.
• Immune KPI: mKRAS-specific T-cell fold-change; ROC-derived threshold around 9.17×.
• Main finding: Above-threshold responses associated with better RFS/OS and higher rates of ctDNA clearance.
• Next step: Broader coverage via 7P (KRAS/NRAS G12/G13) in an ongoing randomized Phase 2.

2. Study Design & Population

• Design: Multicenter, single-arm Phase 1 (safety, immunogenicity, exploratory efficacy), prime plus boosts.
• Population: PDAC-heavy cohort with MRD positivity (ctDNA/tumor markers) after surgery and standard care.
• Delivery: Albumin-binding amphiphile → subcutaneous dosing → lymph-node accumulation and dendritic-cell presentation.

The strategic choice of the adjuvant MRD window—minimal tumor burden—reduces immunologic friction and favors T-cell priming.

3. Endpoints: Immune, Molecular, Clinical

• Immune: mKRAS-specific CD4/CD8 by ELISpot/ICS; fold-change as primary KPI.
• Molecular: ctDNA dynamics (negativity/clearance) as a surrogate.
• Clinical: RFS and OS explored.

4. Key Results: Threshold, ctDNA, Survival

• Immune threshold: ~9.17× fold-change associated with statistically improved RFS/OS.
• ctDNA: Above-threshold responders showed high rates of ctDNA negativity.
• Survival: Cohort-level mRFS ~16 months and mOS ~29 months range; PDAC subset shows consistent trends.

Bottom line: achieving a sufficient T-cell “dose” aligns improvements across molecular (ctDNA) and clinical (RFS/OS) outcomes—quantitatively linking immune kinetics to benefit.

5. Response Quality & Antigen Spreading

• Quality: High rate of dual CD4/CD8 priming with effector molecules and memory phenotypes.
• Spreading: Frequent antigen spreading to patient-specific non-vaccine mutations.

This suggests a shift from point control to area control across clonal diversity, supporting durability.

6. Safety & Implementability

• Safety: No prominent novel signals; mostly local reactions and mild-to-moderate systemic AEs.
• Ops: Outpatient-friendly subcutaneous dosing with ctDNA monitoring.

7. Limitations & Generalizability

• Single-arm, small N: Uncertainty remains in effect size estimation.
• Threshold portability: ~9.17× is data-derived under this study’s context; prospective validation in randomized trials is essential.
• Coverage/HLA: 2P → 7P expansion broadens eligibility but requires site-level genomics/ctDNA/immune monitoring workflows.

8. Implications for Practice & Development

General / Beginners

• Detect post-op MRD via ctDNA and vaccinate to delay relapse.
• Favorable safety; outpatient schedules are feasible.

Researchers / Biotech / Clinicians

• Prospective validation of the immune KPI → outcome link (randomization, stratification, ctDNA endpoints).
• Enhance spreading and memory CD8 quality via combinations (low-dose chemo, RT, ICI sequencing).
• Scale eligibility (HLA/mutations) and supply under 7P.

9. FAQ

Why focus on MRD?

Lower tumor burden favors immune leverage, and ctDNA enables early, measurable response tracking. Is ~9.17× a fixed threshold?

It’s an ROC-optimized value in this dataset; prospective validation in randomized settings is required. What improves when moving from 2P to 7P?

Broader G12/G13 coverage (KRAS/NRAS) increases eligible population and the probability of area control.

10. Outlook (Editorial View)

A forward-validated composite surrogate—(i) immune threshold, (ii) ctDNA negativity, (iii) breadth of spreading—could accelerate Phase 3 design, label expansion, and real-world adoption. Sequencing matters: vaccine-first → ICI-follow and immune “ground-prep” with low-dose chemo deserve priority testing. Hospital workflows that integrate pathology, genomics, ctDNA, and immune monitoring will likely anchor post-op standards.

(This article was edited by the Morningglorysciences team.)