‘Time to rethink’ when patients with cancer enroll in early-phase trials, researchers argue
Key takeaways:
- Researchers contend that patients with incurable cancer should be enrolled in early phase trials at a time when they are in a good remission
- This approach also provides more options in the event of treatment failure.
Patients with advanced cancer should be enrolled in early phase clinical trials during favorable points in their disease rather than after exhausting standard-of-care treatments, according to a paper published in JCO Oncology Practice.
The authors likened the situation to a pilot trying to right the course of an airplane experiencing mechanical problems. The best time to attempt such a correction would be while the plane is at cruising altitude rather than when it is “nosediving at 2,000 feet,” they wrote.
“We believe it’s important to expose patients to early-phase trials sooner, when they’re in good shape, so then we can stabilize and salvage them if they do not respond to or benefit from an experimental treatment,” co-author Farshid Dayyani, MD, PhD, medical director at Stern Center for Cancer Clinical Trials and Research at University of California Irvine Chao Family Comprehensive Cancer Center, told Healio. “We think it’s more reasonable and fairer to patients to expose them to a potentially transformative new treatment, but have a safety net if they don’t respond.”
Healio spoke with Dayyani about the changes he and his colleagues propose, how they might help patients, and potential barriers and counterarguments to this approach.
Healio: What are the enrollment guidelines for early phase clinical trials?
Dayyani: Phase 1, first-in-human trials are dose-finding safety studies to determine what dose is tolerated. The next step is to go to the phase 2 trial to look for efficacy. Traditionally, enrollment requires that patients have gone through all standard treatments or are no longer eligible for standard treatments. That’s when they are supposed to enroll in a phase 1 trial.
Notably, because these are novel compounds and the main purpose is to establish their safety profile, adverse events and toxicity profile, the bar to enroll is fairly high. By and large, the criteria call for well-preserved liver, kidney and bone marrow function and good performance status. So, it’s a preselection of patients who might not actually represent the patients we would then see in real-world practice. These are patients who went through all standard-of-care treatments and are still well and fit enough to enroll in a trial meant to describe the toxicity profile of that compound or combination.
I do think the landscape is changing, because we’re moving from empiric, nontargeted systemic treatments to much more rationally designed, targeted treatments that show good efficacy even in an early phase.
Healio: Why should patients be enrolled in these trials sooner?
Dayyani: The paper focuses on diseases that are aggressive with no known cure, with very limited standard-of-care options, so it doesn’t necessarily apply to highly curable, early-stage disease.
However, in cancers like pancreatic adenocarcinoma, for example, we now have these novel targeted therapies, such as inhibitors of the KRAS pathway. We’ve seen in single-arm, early phase studies of these therapies that approximately four to seven out of 10 patients have some sort of tumor shrinkage. This is such an important sign of efficacy. Nothing else in 30 years of pancreatic cancer has shown that, and it likely will revolutionize how pancreatic cancer will be treated in the future. It might actually be a chemotherapy-free regimen.
Now, imagine you have a patient who has to go through an excruciating triplet regimen with a lot of toxicities. The tumor has to grow, and that patient has to go on a different doublet regimen, where the bone marrow is being hit hard again. During this time the disease is progressing. Only when the patient is on the brink of death do we then say, “OK, now you are eligible to try this drug, when we already know seven out of 10 will probably have tumor shrinkage.”
Our point is, why not induce a good response upfront, control the disease, shrink the tumor and reset the clock? This is a disease where in 2, 3 or 4 months, it will invariably start growing again. Why wouldn’t we try a novel mechanism of action at the time of best response?
Healio: What are the counterarguments to your proposed strategy?
Dayyani: One counterargument is that if the patient progresses on the novel therapy, they might not be able to benefit from standard-of-care treatments that are otherwise accessible.
We believe it’s time to rethink how we establish whether a patient is benefiting from treatment in terms of tumor control. That’s where we make the argument that with liquid biopsy or circulating tumor DNA, we are very confidently able to predict early — within 2 to 4 weeks of starting treatment — whether or not the patient is going in the right direction. We need to change our minds in terms of waiting 8 weeks to do a scan and have that tumor grow by 20% before we take the patient off that drug.
Healio: Are there any other potential barriers?
Dayyani: I do think it will be important to revise how we assess response in terms of surrogate markers to predict response radiographically. We don’t want to expose patients to an ineffective experimental treatment and have them deteriorate to a point where they cannot get the standard-of-care treatment.
We need to monitor closely and be able to take them off these experimental drugs if needed. Some investigators might not be OK with taking someone off treatment within 3 to 4 weeks if the protocol says to wait 6 to 8 weeks before the next scan. I think the mindset needs to change — we need to be nimbler in predicting whether or not a patient is benefiting.
Another obvious concern is that if there is unforeseen severe grade 4 or grade 5 toxicity, the patient won’t be able to be exposed to the next standard-of-care treatment they would have received if they’d just gone through the lines of treatment. This is a risk/benefit calculation, and it’s a discussion we have to have with our patients.
Healio: What else would you like to emphasize?
Dayyani: We acknowledge that the landscape is changing. Many of the novel phase 1 trials allow earlier enrollment. We at UC Irvine now have trials with novel agents based on mutations that allow enrollment in treatment-naive patients. I think that is fantastic, because we know what standard chemotherapy does in that disease.
We have seen early phase efficacy with these novel compounds, and it makes sense to try them in the earlier line of treatment. I think the landscape is changing for the better.
For more information:
Farshid Dayyani, MD, PhD, can be reached at fdayyani@hs.uci.edu.
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