Designing and Managing Phase 2 Trials for Immunotherapy: Key Considerations

Introduction

Immunotherapy has transformed the treatment landscape for various cancers, autoimmune diseases, and chronic infections. As these therapies work by modulating the body’s immune system, Phase 2 trials for immunotherapies require distinct strategies that account for delayed responses, novel endpoints, and immune-related adverse events (irAEs). This tutorial outlines the key scientific, operational, and regulatory considerations in planning and executing Phase 2 trials for immunotherapy agents.

Unique Characteristics of Immunotherapy in Phase 2

• Delayed or atypical response patterns: Tumor growth may precede shrinkage (pseudoprogression)
• Immune-related toxicity: Includes colitis, hepatitis, pneumonitis, and endocrinopathies
• Durable responses: May occur even in patients who stop treatment early
• Biomarker complexity: PD-L1, tumor mutational burden (TMB), and T-cell infiltration are evolving targets

Endpoint Selection in Immunotherapy Trials

1. Objective Response Rate (ORR)

• Common in single-arm Phase 2 oncology trials
• Should be evaluated using immune-related RECIST (iRECIST) or immune-modified WHO criteria

2. Duration of Response (DoR)

• Important when short-term ORR underestimates long-term benefit

3. Progression-Free Survival (PFS)

• Should account for pseudoprogression; iRECIST provides confirmation rules

4. Immune Biomarker Response

• Exploratory endpoints such as cytokine levels, tumor-infiltrating lymphocytes (TILs), or T-cell activation markers

Dose-Finding Strategies

• Flat dosing or weight-based fixed dosing often used for monoclonal antibodies
• Dose escalation based on immune activation biomarkers may complement MTD-based approaches

Patient Selection and Stratification

• Use of PD-L1 or other biomarker status to enrich populations
• Baseline immune profiling can help stratify patients by response likelihood
• Avoid over-restrictive criteria to capture real-world heterogeneity

Management of Immune-Related Adverse Events (irAEs)

• Must establish protocols for early detection and management
• Use CTCAE v5.0 for grading; steroids and immune suppressants as standard treatment
• Longer safety follow-up windows may be necessary

Trial Designs Suited for Immunotherapy in Phase 2

1. Simon’s Two-Stage Design

• Useful for early decision-making on efficacy
• Can terminate for futility if ORR is below threshold after stage one

2. Basket Trials

• Explore single immunotherapy in multiple tumor types with a shared biomarker

3. Expansion Cohorts

• Used after identifying a signal in Phase 1B or early Phase 2
• Can add biomarker-negative or combination arms

Immunotherapy Biomarkers in Phase 2

• PD-L1 Expression: Companion diagnostic in multiple cancer indications
• Microsatellite Instability (MSI): Predicts response in colorectal and other cancers
• Tumor Mutational Burden (TMB): Emerging marker with mixed regulatory support
• Peripheral immune cell subsets: Flow cytometry or CyTOF-based analysis

Regulatory Guidance and Feedback

FDA (U.S.)

• Supports use of ORR with DoR in accelerated approval programs
• Encourages early dialogue when novel biomarkers or endpoints are used

EMA (Europe)

• Recommends hierarchical or co-primary endpoint approaches when using novel endpoints
• Allows biomarker-enriched Phase 2 trials if substantiated by robust rationale

CDSCO (India)

• Requires biomarker stratification justification in oncology trials
• Mandates post-marketing safety follow-up for immunotherapy products

Data Monitoring and Risk Mitigation

• Independent Data Monitoring Committees (IDMC) recommended due to potential late toxicities
• Implement real-time AE monitoring dashboards
• Train investigators on recognizing and managing irAEs

Best Practices

• Use immune-specific response criteria in protocol and analysis plans
• Incorporate biomarker-driven stratification at study outset
• Ensure long-term follow-up for delayed adverse events and survival benefits
• Use imaging central review when evaluating atypical responses

Conclusion

Immunotherapy trials in Phase 2 require adaptive thinking, modified response assessments, and specialized safety oversight. By understanding the immune mechanisms involved, selecting appropriate endpoints, and preparing for unique toxicity profiles, sponsors can design effective and regulatory-compliant studies. The evolving nature of immuno-oncology and chronic disease immunotherapies demands trial models that are as dynamic and precise as the treatments themselves.