Developing New Clinical Endpoints for Immuno-Oncology Studies

The unique mechanism of action of immuno-oncology treatments necessitates rethinking of traditional clinical trial endpoints. Although overall survival remains the most compelling primary endpoint, achieving it requires years of study and would delay the approval of life-saving or extending treatments. Thus, drug developers are using surrogate endpoints to monitor the effectiveness of immunotherapies, taking into account the differences between immunotherapy and traditional treatments.

Existing standards for determining the effectiveness of treatment were developed with traditional chemotherapy in mind. Because the initial response to effective chemotherapy drugs has been decreased tumor mass, standards such as Response Evaluation Criteria in Solid Tumors (RECIST) were based on reduction of total tumor burden. Criteria such as change in the sum of the longest diameter of each measurable tumor lesion are useful for traditional chemotherapeutic agents, but may not accurately reflect response to immunotherapeutic treatments.

Immunotherapy drugs are not adequately served by tumor burden measures because the disease may appear to progress or flare up before showing a response to treatment. T-cell infiltration can increase the apparent size of tumors in imaging. In the initial stages of treatment, a biopsy would be required to demonstrate that the increase in tumor size does not represent disease progression. Thus, an initial response to immunotherapy treatment is not accurately captured by RECIST standards that rely on tumor burden.

In 2009, during the Phase II trials of ipilimumab, a monoclonal antibody for the treatment of melanoma, investigators proposed a new set of immune-related response criteria (irRC) to better measure the effectiveness of immunotherapy treatments. Four response patterns associated with favorable survival were proposed: “(a) shrinkage in baseline lesions, without new lesions; (b) durable stable disease (in some patients followed by a slow, steady decline in total tumor burden); (c) response after an increase in total tumor burden; and (d) response in the presence of new lesions.”1 The notable addition of a time dimension in irRC helped differentiate disease progression from a temporary flare effect.  
 
Although irRC more accurately measured immunotherapy endpoints, the standards introduced a degree of ambiguity. In 2014, irRECIST was proposed as a new standard that improved upon irRC “to allow for treatment evaluations and assessments that better meets both investigators' and patients' needs.” As a result, the standard would also better reflect sponsors' demands for more reliable and reproducible study data analyses.2 By creating more objective assessments, irRECIST aims to serve as a reproducible standard for clinical trials with immunotherapy drugs. If the clinical relevance of irRECIST is confirmed, it will allow for independent central review of findings.

Early and late phase trials

The challenges in defining clinical endpoints presented by the mechanism of action of immunotherapeutic agents differentially affects early and late phase studies.

Surrogate endpoints such as overall response rate (ORR), progression-free survival (PFS), and duration of response (DoR) can be used to achieve regulatory approval, provided that they are able to predict clinical benefits. Indeed, surrogate endpoints have been allowed in the FDA accelerated approval pathway since 1992, and two immunotherapy treatments, pembrolizumab and nivolumab, have been approved based on surrogate endpoints that include ORR and DoR.

When planning early phase studies, primary endpoints almost always focus on safety, pharmacokinetics (PK) and pharmacodynamics (PD). The broad purpose of choosing these endpoints is to ensure that the drug is engaging its target in vivo, and to select a maximum tolerated dose (MTD). Often in immuno-oncology studies, MTD is not reached.  Therefore, the clinically effective dose is chosen, identified by pharmacokinetic parameters such as area under the concentration-time curve (AUC).

It is also fairly common for early phase studies to include surrogate efficacy endpoints, such as ORR, PFS and DoR, as secondary or exploratory measures. Dose expansion phases frequently include several arms of potential therapeutic targets. The intent is to capture early hints at efficacy to help inform future drug development. Strong efficacy results may even lead to breakthrough therapy designation, which can accelerate market registration.  

In late phase programs, the use of overall survival as a primary endpoint has declined in favor of the surrogate endpoints described above. Though overall survival is almost always included and ultimately remains the most important patient outcome, it is more often a secondary endpoint. This change is driven by expedited approval pathways where regulatory agencies grant initial approval contingent on post-approval commitments to demonstrate a favorable effect on overall survival. Greater understanding of the mechanisms of action that drive response to immuno-oncology treatments enables modification of these surrogate endpoints based on specific drugs. For example, normalization of the levels of CA125 marker may be used as a surrogate endpoint for ovarian cancer therapies.

With our improved understanding of the process of an immune response, especially in solid tumors, we have variations on standard measurement of response that require serial radiological assessment of tumors to confirm if the tumor is, indeed, growing in size, or if the increase in size is the first step in an immune response within the tumor.  

Quality of life

As immunotherapeutic agents have shown a remarkable ability to extend a patient’s life, another key endpoint to consider is quality of life (QoL). Some effective treatments may produce side effects such as GI symptoms or skin reactions that patients cannot tolerate over lengthy treatment periods. The FDA and EMA have also issued guidance documents over the past decade requesting QoL data in the form of patient-reported outcome (PRO) endpoints, and have approved many products with PRO endpoints in labeling. Finally, biopharmaceutical companies may find QoL data to be useful when negotiating reimbursement, and to differentiate a treatment for standard of care.  

Future directions

Although several immunotherapy trials have demonstrated significant improvements in overall survival, years of follow-up study are required to demonstrate definitive overall survival results in many oncology indications. This approach impedes potentially life-saving or life-extending treatments from reaching the market. The challenge, then, will be to identify surrogate endpoints that predict overall survival. The scientific community is actively engaged in identifying reliable endpoints that can be used in place of overall survival for drug approvals. One area of research that is yielding promising results is in the study of cancer biomarkers. However, until these biomarkers can be demonstrated to be an accurate predictor of treatment effects, overall survival will likely remain the gold standard endpoint for drug approvals for the foreseeable future.

Chris Smyth, PhD, is Executive Vice President, Oncology and Joy Yucaitis is Senior Director, Oncology Strategy at Novella Clinical.

• “Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria.” Clin Cancer Res. 2009 Dec 1;15(23):7412-20. doi: 10.1158/1078-0432.CCR-09-1624. Epub 2009 Nov 24.

• “Adaptation of the immune related response criteria: irRECIST.” OncologyPro, www.oncologypro.esmo.org/Meeting-Resources/ESMO-2014/Immunotherapy-of-Cancer/Adaptation-of-the-immune-related-response-criteria-irRECIST. Accessed 16 Februrary 2017.