Immuno-Oncology Requires a More Comprehensive Approach for the Assessment of Clinical Endpoints

Reshaping measures to recognize the potential of Immuno-Oncology
(I-O)

The criteria used to assess the potential benefit of cancer therapies are based on traditional treatments such as surgery, radiation therapy, and chemotherapy¹
Because I-O is a fundamentally different way to fight cancer,² a more comprehensive approach to endpoint assessment is needed to recognize its potential benefit^3-6

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OS and PFS are two of the most common endpoints to assess clinical benefit

Traditionally,
overall survival (OS),
progression-free survival (PFS), and overall response rate (ORR) are among the endpoints used to measure outcomes in oncology research^7,8
As oncology research aims to prolong patients’ lives, OS is the gold standard for assessing therapeutic benefit^7,8

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Magnitude and duration are both key measures of response

Therapeutic response can be assessed by both magnitude (size) and duration (time)⁷

ORR is the proportion of patients with a predefined decrease in tumor burden⁷

It reflects solely the magnitude of response and is generally defined as a sum of partial and complete responses⁷

Duration of response (DOR) measures the time from initial tumor response to disease progression⁷

As our understanding of clinical outcomes continues to evolve, DOR may prove to be even more relevant to potential benefit than the magnitude of tumor reduction⁸

Because responses range in both size and duration, these measures should be evaluated together to more accurately assess advances in I-O research⁷

Example waterfall plots capturing ORR data

The graphs are examples of waterfall plots capturing ORR data. In this example, each vertical bar represents an individual patient’s change in tumor burden from baseline.^7,9

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Assessing multiple measures can illustrate the full scope of clinical benefit

Diagram of specific measures to assess across the duration of a clinical trial

Assessing measures across the entire duration of the trial and at particular time points of interest may help to more fully understand the potential benefit of immunotherapies^3-5,10
These measures include median duration, time-point analyses, and hazard ratio (HR)/relative risk reduction (RRR)^3-5,10,11

Each measure provides a unique perspective on treatment benefit

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KM curves reflect multiple measures of survival

Kaplan-Meier (KM) survival curves integrate median duration, time-point analyses, and HR^5,10,12
Assessment of these measures in combination can provide a broad picture of the difference between the investigational arm and the control arm with respect to PFS and OS, as in the 2 hypothetical randomized controlled clinical trials below^3-5,10,13

Kaplan-Meier (KM) curve representing probability of PFS/OS with median duration, landmark analysis, and hazard ration/relative risk reduction integration

*A log-rank test is conducted to determine statistical significance between arms (represented by a P value).¹⁴

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Other measures may provide additional information regarding clinical benefit

Treatment-free survival (TFS) is the time that patients in a given treatment arm spent off treatment prior to initiating a subsequent therapy^15,16

TFS can be defined as the area between two KM curves, one representing the time until initiation of a subsequent therapy or death, and the other the time until patients stop their protocol¹⁵
TFS may be reported in months or a proportion of the overall study time period and assessed in the intent-to-treat (ITT) population¹⁵
TFS may integrate patient quality of life and toxicities experienced during the treatment-free period^15,16
This is in contrast to treatment-free interval (TFI), which is defined as time from treatment discontinuation until initiation of a subsequent therapy^15-18

Time after cessation of IO protocol therapy without toxicity, before initiation of subsequent systemic anticancer therapy or death.

†

Time after cessation of IO protocol therapy with toxicity while treatment-free.

‡

Includes toxicity persisting since protocol therapy and toxicity newly presenting after protocol therapy cessation.

Patient Reported Outcomes(PROs) assess a patient’s health-related quality of life (HRQOL) physically, psychologically, and socially, as experienced by the patient without the interpretation of a clinician^19,20

PRO assessments are increasing in prominence as secondary endpoints or even as primary endpoints^19-21
PROs may help inform treatment decisions by evaluating the impact of a therapy on the patient²²

Validated, general assessments, such as the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), can assess any patient with cancer, or clinicians may choose to provide tumor-specific questionnaires for patients²³

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Immuno-Oncology Requires a More Comprehensive Approach for the Assessment of Clinical Endpoints

Immune Pathways

I-O Biomarkers

References–Endpoint considerations for I-O research