Rethinking Cancer Treatment: Are We Measuring Success the Right Way?
"Why Immuno-Oncology Demands a New Approach to Clinical Trial Endpoints"
For decades, cancer treatment has largely relied on therapies like chemotherapy and targeted agents. Clinical trials evaluating these treatments have focused on assessing tumor shrinkage and delaying disease progression. However, a new class of drugs, called immune-oncology (I-O) agents, is changing the game. These therapies work by harnessing the power of the immune system to fight cancer, and they often exhibit unique response patterns that traditional clinical trial endpoints may miss.
The rise of I-O has created a need to rethink how we measure success in cancer treatment. Traditional metrics, such as overall response rate (ORR) and progression-free survival (PFS), may not accurately reflect the long-term benefits that I-O agents can provide. In some cases, tumors may initially appear to grow before shrinking, or patients may experience delayed but durable responses. This has led researchers to explore novel endpoints that can better capture the activity of I-O agents.
This article explores the challenges of using traditional endpoints in I-O clinical trials and discusses potential new approaches to evaluating the effectiveness of these innovative therapies. By understanding these challenges and embracing new endpoints, we can better develop and utilize I-O agents to improve outcomes for cancer patients.
The Problem with Traditional Endpoints
Traditional clinical trial endpoints like ORR and PFS are based on measuring tumor size. While these metrics are useful for evaluating cytotoxic therapies that directly kill cancer cells, they may not be as relevant for I-O agents, which work indirectly by stimulating the immune system. This can create a number of challenges:
- Delayed Responses: I-O agents may take time to activate the immune system, leading to delayed responses that wouldn't be captured by traditional endpoints.
- Durable Responses: I-O agents can produce long-lasting responses, even after treatment has stopped. Traditional endpoints, which focus on short-term tumor changes, may not reflect these durable benefits.
- Non-Linear Dose-Response: The relationship between the dose of an I-O agent and its effect on the tumor may not be linear. This makes it difficult to determine the optimal dose using traditional dose-escalation methods.
Redefining Success: Novel Endpoints for I-O Trials
To address the limitations of traditional endpoints, researchers are investigating novel approaches to evaluating I-O agents. These include:
<ul> <li>Immune-Related Response Criteria (irRC): These criteria account for pseudoprogression and allow for the assessment of overall tumor burden, including new lesions.</li> <li>Biomarkers: Biomarkers, such as PD-L1 expression and tumor mutational burden (TMB), can help predict which patients are most likely to respond to I-O therapy.</li> <li>Patient-Reported Outcomes (PROs): PROs capture the patient's perspective on their health and well-being, which can provide valuable insights into the benefits of I-O therapy.</li> <li>Milestone Survival: Looking at survival rates at specific time points (e.g., 1 year, 2 years) to capture the long-term benefit that I-O agents can provide, even if traditional endpoints don't show an immediate response.</li> </ul>
By incorporating these novel endpoints into clinical trials, researchers can gain a more complete understanding of the activity of I-O agents and better identify patients who are most likely to benefit from these therapies. This will ultimately lead to more effective use of I-O agents and improved outcomes for cancer patients.