SAN DIEGO — Rapid progress from targeted therapies for cancer are changing how clinical trials are conducted and, in the process, raising new challenges for researchers and drug companies.
Today, approvals for new cancer drugs are often supported by data from only a few hundred patients or fewer, who are carefully screened and selected for genetic abnormalities made targetable by advances in sequencing and therapeutics. Undeniably good news for those patients, the shift is also spurring a re-think in study design.
"Modernizing the clinical trial infrastructure is a really important challenge for cancer research right now," said Ned Sharpless, director of the National Cancer Institute, in an interview with BioPharma Dive at the American Society of Hematology's annual meeting in San Diego.
Sharpless compared the expansive clinical studies used to test chemotherapies to recent datasets that have showed impressive benefit with far fewer patients.
"The reason that is occurring is because — rather than having 1,000-patient trials where everyone is heterogeneous and the delta between outcomes is 2% — we are doing 80-person trials or 120-patient trials, but they're all molecularly defined," he said. "We're comparing apples to apples and not apples to oranges."
Take acute myeloid leukemia, or AML. Japanese drugmaker Astellas needed efficacy data from only 138 patients to convince the Food and Drug Administration to approve its drug Xospata late last month. Xospata targets a mutation known as FLT3 found in about 25% or 30% of AML patients.
Xospata's only the latest in a slate of drugs the FDA has cleared for use in AML, which remains in serious need of new treatment options. Five of the eight approved since 2017 target a specific mutation or antigen expressed by the cancer, and were supported by trials that enrolled between 174 and 717 patients.
The difficulty, Sharpless said, is that genetically defined trials can be much more complicated to administer, requiring the screening of hundreds or thousands of patients to enroll a study with narrowly defined inclusion criteria.
For that very reason, next-generation sequencing has become a crucial element of cancer research. But that brings challenges in cost as well as access.
"We need to understand how to use next-generation sequencing. It's a costly test and it leads to the use of costly drugs," Sharpless said. "There are a lot of challenges related to the broad, widespread implementation of next-generation sequencing."
In a speech given later on Saturday, Sharpless pointed to one study that found the presence of p53 mutations in AML patients determines how well they respond to a standard chemotherapy. But that signal had gone unnoticed for years, a fact the NCI head described as a failure of data aggregation.
"If we'd aggregated data and we'd start putting large collections of AML patients together that had been genetically sequenced, this result, and many other results, would have been apparent almost immediately," Sharpless said in his speech.
Sharing data and real-world evidence isn't a given, though, especially if it's held by private payers or drug companies for commercial use.
Highly active targeted therapies also raise questions about how to appropriately construct a control arm in clinical testing.
If early testing shows dramatic and clear responses to therapy, assigning hundreds of patients to a chemotherapy or other standard therapy arm may no longer be ethical.
"There's nothing more convincing than randomized, controlled trials, but there's also this issue of equipoise," said Sharpless to BioPharma Dive, referring to the principle that researchers should be genuinely uncertain of which study group will see a greater benefit.
Returning to the AML example, studies supporting approval of Celgene and Agios' Idhifa and Agios' Tibsovo were single-arm trials, while those supporting Venclexta were open-label.
In response, researchers are also turning to newer clinical trial designs, like the "umbrella" format used in the Beat AML study sponsored by the Leukemia and Lymphoma Society.
Patients enrolled into Beat AML were genetically profiled before being assigned to an experimental targeted therapy. An initial report will be presented at ASH on Monday morning.
Still, while sequencing and targeted therapy can make more personalized studies possible, clinical benefit isn't guaranteed to follow.
"We've had some really impressive and important progress, but it has been uneven," Sharpless said, noting the recent approvals in AML are more "singles" or "doubles" rather than curative "home runs."