Addressing resistance to PD-1/PD-(L)1 pathway inhibition: considerations for combinatorial clinical trial designs

Area of Science:

• Oncology
• Immunotherapy
• Clinical Trial Design

Background:

• Increasing use of PD-(L)1 inhibitors across various cancer types and treatment settings.
• Significant unmet need for therapeutic strategies to address primary and acquired resistance to PD-(L)1 blockade.
• Melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC) have extensive clinical experience with PD-1 pathway blockade and associated resistance.

Purpose of the Study:

• To address challenges in developing effective therapies for patients previously treated with anti-PD-(L)1 agents.
• To provide recommendations for designing clinical trials in the setting of PD-(L)1 resistance.
• To focus on eligibility criteria, comparators, endpoints, and tumor-specific combination therapy designs.

Main Methods:

• A year-long collaborative effort involving six non-profit patient organizations.
• A 2-day workshop with academic, industry, and regulatory participants.
• Discussion and consensus-building on key themes for clinical trial design.

Main Results:

• Identified key discussion themes and positions regarding therapeutic approaches for PD-(L)1 resistant cancers.
• Focused on critical elements of clinical trial design including eligibility, comparators, and endpoints.
• Proposed tumor-specific strategies for combination therapies in melanoma, NSCLC, and RCC.

Conclusions:

• Consensus reached on critical considerations for advancing clinical trials in PD-(L)1 resistant settings.
• Recommendations aim to accelerate the development of novel combination therapies for patients with limited options.
• The manuscript provides a framework for future research and drug development in immuno-oncology resistance.