Expedited approval of the use of new TKIs in CML Sparks issues

US regulators’ use of a rapid release route for a new lead indication of asciminib in chronic myelogenous leukemia (CML) has raised questions due to the number of drugs already available for the disease.

In October, the US Food and Drug Administration (FDA) granted accelerated approval for asciminib (Scemblix, Novartis AG) for adult patients with newly diagnosed chronic phase Philadelphia chromosome-positive CML.

Asciminib is one of six tyrosine kinase inhibitor (TKI) drugs used in CML, a class that began with the introduction of imatinib (Gleevec) in 2001. By 2016, researchers reported that TKIs had helped bring the life expectancy of patients with CML closer to that of the general population. Doctors and patients now have several options for second-generation TKI drugs that can also be used in newly diagnosed patients, as well as the option to start with the cheaper option, imatinib.

The FDA established the accelerated approval pathway in 1992 to expedite the introduction of drugs to the market for serious diseases that address unmet medical needs.

The agency and companies are essentially banking on promising study results, often using surrogate markers, to allow drugs to be sold while they wait for evidence from confirmatory studies. For example, in August, the FDA used the accelerated approval process to clear the first T-cell receptor gene therapy for certain advanced forms of sarcomas, a type of cancer with limited treatment options.

The next accelerated approval of a cancer drug was the indication for asciminib as first-line therapy. The FDA also used accelerated approval for the initial approval of asciminib in 2021 for use in CML previously treated with two or more TKIs. By 2022, Novartis was able to provide sufficient evidence of the drug’s effectiveness to receive full approval for the drug for this use.

The timeframe for expected confirmatory research for asciminib as first-line therapy is longer, with a deadline of 2028 for this work. Data presented so far on asciminib have failed to convince some oncologists of the need for rapid approval for frontline use.

“The result is a drug that appears to be as good as other second-generation TKIs,” says Mikkael A. Sekeres, MD, MS, chief of the division of hematology at the Sylvester Comprehensive Cancer Center of the University of Miami Health System, Miami. “I don’t know how they could use the expedited approval mechanism to get this passed.”

Sekeres, a former chair of the Oncologic Drugs Advisory Committee, addressed the concerns and challenges associated with using the accelerated approval process in his 2022 book: Drugs and the FDA: Safety, Effectiveness, and Public Trust.

“The purpose of the accelerated approval mechanism is to introduce a new therapy to treat a serious disease in a way that others have not done so far where there are no existing options,” Sekeres said.

This is a markedly different situation than CML, where medications have improved dramatically in the 21st century, unlike many other cancers treated by hematologists.

“As someone who specializes in treating people with leukemia, every hospital day of my life I would be happy if all my patients came in with chronic myelogenous leukemia in the chronic phase,” he said, rather than other cancers these robust treatment options are lacking.

In CML, doctors choose among TKIs taking into account patients’ side effects and other health concerns, and in some cases also weighing the impact of financial toxicity, he said.

“If I have a patient with chronic myeloid leukemia in the chronic phase, I treat him with imatinib,said Sekeres.

Questions about replacement endpoints

Sekeres is not alone in questioning the use of the expedited FDA pathway for a new indication for a TKI in CML.

“Where is the ‘unmet need’ that warrants accelerated approval in this environment?” wrote Timothée Olivier, MD, who is affiliated with both the Hôpitaux universitaires de Genève and the VK Prasad Laboratory funded by Vinay Prasad, MD, MPH, in one Post from November 3rd on X.

Olivier, Prasad and co-authors in a September correspondence to the American Journal of Hematology asked questions about study design for a key asciminib trial, ASC4FIRST. They identified what they believed to be a vulnerability in the endpoints used.

“Molecular milestones such as the 48-week MMR (measles-mumps-rubella vaccination) are commonly used in clinical trials due to their convenience and shorter time frame for evaluation,” they wrote. “However, these milestones are not definitive indicators of long-term survival or overall clinical benefit.”

In recent years, there has been increasing concern about the evidence gap between the first accelerated approvals and the completion of studies showing whether these promising therapies actually help patients live longer or better lives. Researchers including Bishal Gyawali, MD, PhD, a Medscape Medical News One contributor also questioned the level of reliance on replacement endpoints in expedited approvals.

In response, the FDA’s cancer division and the U.S. Congress have taken steps to force drugmakers to more quickly answer the key question in accelerated approvals: Does this drug provide the expected benefits? For example, in March, the FDA appears to have rejected an offer for accelerated approval of a lymphoma drug due to concerns about the timing of completion of confirmatory research.

The use of accelerated approval will continue to be a balancing act, due in part to demand for newer agents, Ravi Bhatia, MD, of the O’Neal Comprehensive Cancer Center at the University of Alabama at Birmingham, said in an email Medscape Medical News.

“Accelerated approval of agents for the pretreatment of CML does not appear to be justified given the high efficacy of existing agents,” said Bhatia, vice chair of the National Comprehensive Cancer Network’s Clinical Practice Guidelines in Oncology Panel for Chronic Myeloid Leukemia.

“On the other hand, there is greater urgency to develop agents for patients where existing agents have failed and for patients with advanced disease, and the use of accelerated approval may be warranted in this setting,” Bhatia said.

In an interview with Medscape Medical NewsRichard A. Larson, MD, professor in the Division of Hematology/Oncology at the University of Chicago, Chicago, and ASC4FIRST investigator, noted that the study’s 96-week follow-up data will be presented at the annual meeting American Society of Hematology in San Diego in December.

Larson said data from this study shows sustained benefit from frontline use of asciminib. Larson is also the author of a New England Journal of Medicine May article about the ASC4FIRST test.

“The data speak for themselves that asciminib is at least as effective or more effective and at least as well tolerated as what is already on the market,” Larson said. “So ultimately their argument comes down to the cost of a new drug and whether we need a new drug.”

From the perspective of cancer patients, the answer is clear, he said.

“When you talk to cancer patients, they want new drugs to become available as quickly as possible. And I think that was the original reason for the accelerated approval pathway, that a drug that was shown to be safe and effective in a prospective clinical trial could receive accelerated approval based on a surrogate endpoint.”

The remarkable success in developing TKI drugs for CML creates difficulties in testing later subjects in this class because of their longer survival, Larson said.

“If you look at the overall population, the overall survival rate of newly diagnosed CML patients who have all available treatment options is now approximately the same as the survival rate of non-CML patients.”

“For most cancer drugs, the FDA wants an overall survival benefit, but patients with newly diagnosed CML survive for 20 or 30 years and don’t die as quickly as they used to. Therefore, it would be impractical to require a clinical trial to show a survival benefit, a randomized trial.”

“Here, the use of a surrogate endpoint that represents the key molecular response at one year has been so valuable because the drugs have been approved and are getting into patients much sooner than if there was a requirement for a survival endpoint,” he said.

Larson reported affiliations with AbbVie, Amgen, Astellas, Celgene, Cellectis, Curis, CVS Caremark, Daiichi Sankyo, ImmunoGen, Jazz, MorphoSys, Rigel, Servier, Forty Seven/Gilead, Novartis and Rafael Pharmaceuticals. Sekeres announced relationships with the advisory boards of BMS, Kurome and Novartis. Bhatia reported no relevant disclosures.

Kerry Dooley Young is a freelance journalist based in Washington, DC. Follow her LinkedIn And Topics.