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What is the optimal length of time to treat a cancer patient with immunotherapy agents such as PD-1/PD-L1 checkpoint inhibitors? Simply stated, the answer to that question is unknown.
Immunotherapy agents as a class of cancer therapeutics are relatively new. The optimal duration of treatment with agents such as PD-1/PD-L1 checkpoint inhibitors (e.g., pembrolizumab) has yet to be determined or even studied in-depth with randomized controlled clinical trials. Immunotherapy agents can work remarkably well at controlling or eliminating disease for a subset of patients and cancer types. As the science advances and new agents are developed, the overall efficacy of immunotherapy to treat cancer likely will increase.
However, for a patient who is receiving immunotherapy for an advanced, solid tumor, how long should they take these kinds of drugs? Six months, 12 months, three years, indefinitely?
To answer that question, researchers at UPMC Hillman Cancer Center — in late 2019 — launched across the UPMC Hillman Cancer Center Network, a novel phase III randomized controlled clinical trial designed to evaluate and determine the optimal length of treatment with PD-1/PD-L1 checkpoint inhibitors in a broad spectrum of advanced solid malignancies.
Leading the development and implementation of the trial at UPMC Hillman Cancer Center are principal investigator Antoinette Wozniak, MD, FACP, FASCO, Associate Director for Clinical Research at UPMC Hillman Cancer Center, and medical oncologist Vincent Reyes, MD, who is Co-Assistant Medical Director of UPMC Hillman Cancer Center – Medical Oncology Network.
“The question we are trying to answer is one of the great unknowns in oncology right now. We know these agents can work. We also know that these treatments can have acute toxicities. We know less about the longer-term late effects of their use, but we must be cognizant of the potential. Furthermore, we know nothing about how long to use these immunotherapy agents to achieve optimal outcomes,” says Dr. Wozniak. “Filling that gap in our evidence base has the potential to radically alter the landscape of how immunotherapy is used to treat cancer.”
For a variety of reasons, many clinical trials miss their accrual targets. Barriers to participation come in many flavors, on both the patient and the provider side.
“To increase our chances for success — for this trial specifically but for future trials as well — we decided as a system to pilot a new approach to implementing clinical trials across our network of sites,” says Dr. Reyes.
For starters, before the protocol for this new trial was written, the clinical trial team engaged the physician community across the UPMC Hillman Cancer Center network in a survey that asked a number of basic questions about conducting this proposed checkpoint inhibitor length of treatment trial. The research team and UPMC Hillman Cancer Center leadership wanted to gauge the interest level in such a study and to identify potential barriers to patient and provider participation that could be addressed as part of the trial design.
The response to the survey was overwhelmingly positive.
“If you ask any oncologist, they will tell you that they desire never to have a patient take a drug or receive a therapy one day or one regimen more than is necessary to obtain the best possible outcome. It is that sentiment, I believe, that contributed to the overwhelmingly positive response we saw to our pretrial survey,” says Dr. Reyes.
One significant barrier to overcome in the trial design was how best to find the patients. Since the trial protocol is designed to stop the use of immunotherapy at the one-year point in treatment, locating the patients in advance was a crucial part of the study design.
In order to effectively and efficiently find these patients across the UPMC Hillman Cancer Center network, the research team worked with UPMC clinical analytics (led by Chief Analytics Officer Oscar C. Marroquin, MD, FACC) to mine the electronic health record for potential candidates. Knowing who and where the target patient populations are — in advance — allows for enough time to engage the treating physicians and their practice staff, along with the patients themselves, in a discussion about participating in the trial.
“We needed a way to find our potential participants efficiently. Mining the vast trove of data we have collected as a system and a network is the best approach. A more manual approach, such as has been common in the past, is suboptimal at best,” says Dr. Reyes.
As part of the process, an application was developed for use by the clinical research coordinators to find the eligible patients and practices and then electronically prompt the physician or practice to begin the discussion process.
“We took it a few steps further than that. We can collect data not only on who has accrued in the study but also those individuals who declined — and why — which can sometimes be more valuable information. We created simple drop-down selections in the application to record this information. This kind of patient and trial intelligence allows us to be nimble and reflexive, and able to adjust our approach in real-time and for the future. If we see a particular practice that needs more education to help with accrual, we can see that in the application and react. The goals and functions of the application are many, but the overarching theme is to reduce participation barriers,” says Dr. Reyes.
As one can imagine, communications to both treating physicians and patients are crucial in the success of any clinical trial. This is likely more so in a clinical trial in which patients are asked to stop or pause a therapy that may be working well at controlling their disease.
Communications and talking points were developed for all of the key players at the practices in the network — treating physicians, nurses, clinical research coordinators — all of the clinical staff, and, of course, the patients themselves.
As part of the communication development process, the research team engaged a UPMC patient advocacy group for their input and expertise to learn more about what information is crucial to get across to potential participants.
“We also created a webinar that we made mandatory for the advanced practice providers and nurses, so everyone had the same information and level of training. Creating a consistent and trackable method of training, we believe, will ultimately help with accrual and patient confidence in participating in such a novel study,” says Dr. Reyes.
The trial that has been designed and launched is randomizing patients who have stable or responding disease to stop treatment with their PD-1/PD-L1 therapy at one year or to continue their standard of care treatments until there is some manner of disease progression or unacceptable side effects. The primary goal of the study is to determine whether it is feasible to stop immunotherapy after 12 months of treatment.
Within the UPMC system, approximately 2,300 patients received PD-1/PD-L1 therapy for a variety of advanced solid tumors in the year before the start of the trial. It is anticipated that this number will increase as the clinical indications for treatment with these agents also increase.
“As part of the study, and with their permission, we are collecting and banking participant blood samples for future studies. We are collecting samples at the point in which they enter the trial, and then again at a point in time if the participant has disease progression. We are hoping to learn from those samples anything that may be deterministic of their outcomes and to have the samples available for what will likely be further follow-up investigations,” says Dr. Wozniak.
In patients who already have been treated with a PD-1 or PD-L1 inhibitor for one year, the researchers hope to understand the difference in progression-free survival (time to next treatment, progression, or death, whichever occurs first) between patients who stop treatment and patients who continue treatment.
Complete details about the trial can be found at ClinicalTrials.gov under protocol number NCT04157985: Evaluation of the Length of Treatment With PD-1/PD-L1 Inhibitors in Patients With Advanced Solid Tumors.
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