Joshua Hattem and Matt Furlow co-authored this post with Malik Kaman.
To match the rapid changes occurring in cancer therapy development, oncology clinical trials are making a few changes of their own. As contemporary clinical trials break with tradition by infusing new, or different, outcome measures to better assess clinical efficacy, the results are encouraging: Single-arm phase I/II trials are gaining accelerated approvals using overall response rate (ORR) and duration of response (DoR) as proxies for survival and 72% of the oncology treatments reviewed by the FDA since 2006 gained approval based on response rate and progression-free survival endpoints.
In the oncology landscape, we’re watching therapeutic advancements push the limits of what historical measures like ORR can capture. To meet these needs and more, new categories of novel endpoints that measure, 1.) time to events, 2.) depth of response using more sensitive measures of disease, 3.) immune-related endpoints and, 4.) patient-reported outcomes (PROs) are emerging in clinical trials.
Emerging Endpoints in Today’s Oncology Practice
To explore how novel endpoints are perceived by the medical community—and to get a sense of how they’ll shape the development of new oncology treatments—I spoke with Dr. Lee Schwartzberg at the 2018 American Society of Clinical Oncology (ASCO) meeting.
Dr. Schwartzberg, who’s chief of the division of hematology and professor of medicine at the University of Tennessee, and executive director of The West Cancer Center, confirmed that, while overall survival (OS) may still be “the gold standard for any therapy,” it’s “not realistic” in oncology clinical trials. He believes that, in part, we've become “victims of our own success” as cancer therapies continue to get better and better. It’s true that many of the changes that we’re seeing stem from the impracticality of OS, namely the long assessment timelines and the data analysis complexities introduced by crossover studies.
In recent years, we’ve seen more than a few diseases benefit from adding next-generation endpoints to the clinical trial design, including Janssen’s prostate cancer therapy Erleada, which was approved with a new metastasis-free survival endpoint. Because the current generation of surrogate endpoints like progression-free survival (PFS) fell short in this tumor setting, the trial was designed around a more specific measure as a proxy for survival.
Dr. Schwartzberg talked about how biomarkers can be strictly prognostic, strictly predictive or both prognostic and predictive, and pointed to pathologic complete response (pCR) in breast cancer as a good example of a biomarker that has been established as a surrogate marker. “We now have very well-validated meta-analysis that shows that if you get a pCR to a brief course of chemotherapy or whatever the therapy is, you’re going to have better event-free survival and long-term [success],” he said. “That accelerates drug discovery because instead of waiting … for 10 years to see the outcome, you can predict that outcome based on pCR.”
On the Horizon: Emerging Endpoints in Clinical Trials and Beyond
As we look a few years ahead, there are numerous novel endpoints that have the potential to progress clinical trial design if they gain clinical and regulatory acceptance. Clinical trials are beginning to reach beyond the goal of extending survival, for example, by incorporating fixed treatment durations or treatment cessation. The goal, of course, is to create the same clinical benefit with less therapeutic burden and cost.
First, we expect to see the validation and use of minimal residual disease as a surrogate endpoint in more clinical trials and as a biomarker for treatment cessation. Next, we’re seeing more clinical trials include progression after the next line of therapy (PFS2) as a surrogate endpoint. For example, researchers are evaluating the impact of abemaciclib in subsequent treatment by analyzing the time to subsequent chemotherapy and PFS2. The team concluded that adding abemaciclib to fulvestrant (F) or nonsteroidal aromatase inhibitor (NSAI) delayed the start of subsequent chemotherapy, which is a patient-relevant outcome.
As cancer care becomes more personalized, the need to gather first-hand patient perspectives is greater than ever. The use of PROs is increasing as the value that they provide in both the research and clinical settings comes into focus—and even ushered in a new measurement system. The proliferation of mobile and wearable technologies has played a role by simplifying the process of collecting PROs for both patients and providers.
There’s evidence, too, that clinicians are paying more attention to PRO-related analyses and conducting more readouts at major conferences. For his part, Dr. Schwartzberg has been collecting PROs electronically for 15 years. “Both in the clinical trial setting and in the clinical setting, the more we have the patient’s voice included in the way we make decisions and how we’re treating patients, the better it will be,” he said.
We first saw PROs take the mainstage during last year’s plenary session at ASCO, when presenters linked a web-based reporting tool used by metastatic cancer patients with benefits including longer survival. By sending real-time alerts to physicians, patients who used the tool to regularly report symptoms while receiving chemotherapy lived a median of five months longer than those who didn’t use the tool.
Now researchers are devising ways to engage patients with smart watches and other technologies to improve health literacy and to overcome obstacles presented by patients who have difficulty understanding what’s going on during trials. And as a possible means of standardizing pain PROs, the FDA’s INFORMED program is evaluating the use of facial recognition via digital tools to measure pain.
With all of the exciting and fast-paced changes in cancer care, we need to strike a balance between getting medicines to patients quickly vs. demonstrating extended survival in randomized, controlled trials. As investigators begin to adjust clinical trials to meet modern demands with realistic measures, the potential payoffs are huge, with benefits ranging from reduced drug exposure and increased tolerability to improved financial implications and better quality of life.
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