FDA advisers back new endpoint for myeloma approvals, paving way for faster introduction of new drugs

After oncology experts reviewed arguments in favor of a surrogate endpoint to support multiple myeloma drug approvals, drug developers may soon have a new pathway in the R&D journey.

Friday, 12 members of an FDA advisory committee voted unanimously to support the use of minimal residual disease (MRD) as a surrogate endpoint to enable accelerated approvals of new therapies in multiple myeloma.

Given the panel's overwhelming support—and the FDA’s own positive review ahead of the meeting—the agency will likely start incorporating the approach in its regulatory practices soon.

Since surrogate endpoints in clinical trials read out faster than traditional clinical-outcomes endpoints such as progression-free survival (PFS) or overall survival (OS), new therapies could be expected to reach the market sooner under the approach.

Friday’s meeting centered on two separate meta-analyses of past clinical trials. The analyses showed very strong associations demonstrating that myeloma patients who achieved MRD negativity after treatment would likely enjoy a longer progression-free life.

In the MRD approach, doctors or trial investigators search patients’ bone marrow or other body parts for traces of malignant clones. The most commonly used threshold categorizes patients as MRD negative if no cancer is found in 1 in 100,000 cells (10-5).

The meta-analyses were performed by a team led by Carl Ola Landgren, M.D., Ph.D., from the Sylvester Comprehensive Cancer Center, and another group called i2TEAMM, which was brought together by the International Myeloma Foundation.

The analyses were conducted against the backdrop that conventional tumor responses often don’t provide useful information on treatment effects because existing drugs already shrink tumors in almost all newly diagnosed myeloma patients.

In addition, because existing standard-of-care treatments help first-line patients live a median of seven years, it has become increasingly impractical to follow trials until a PFS readout to seek an FDA approval, the researchers argued.

Nevertheless, the FDA and the external advisers both acknowledged that MRD might not perfectly fit with longer-term benefits. They also stressed the importance of evaluating other endpoints such as PFS and OS during an accelerated approval application.

Remaining uncertainties

One key weak point in the case for the surrogate endpoint is that despite a strong patient-level association between MRD negativity at 12 months and improved PFS across the two meta-analyses, the FDA found only a “weak-to-moderate” trial-level association depending on the patient population being examined.

Having a high trial-level association would be ideal, but it’s not necessary for adopting a surrogate endpoint, Rachel Ershler, M.D., an FDA clinical reviewer, pointed out during a Friday presentation. “Very few” oncology endpoints have met this standard, and most endpoints that supported accelerated approvals have either not been assessed for trial-level surrogacy or, if they have been assessed, have a weak association, she noted.

Neil Vasan, M.D., Ph.D., from Columbia University, a breast cancer expert on the FDA advisory committee, pointed to pathological complete response (pCR), which has enabled accelerated approvals for treatments for early breast cancer. The level of MRD’s trial-level associations seen in the two meta-analyses were stronger than those seen for pCR, he noted.

Another concern raised by the expert panel is the potential unintended consequence that opening up the MRD approach may have on drug development. With too much focus on MRD, there’s a risk that drug companies might abandon efficacious drugs that don't show an early MRD signal.

That’s why the FDA is urging biopharma companies to adopt the “single trial” approach, in which the same randomized study is used to support both an accelerated approval and the full nod, FDA’s oncology chief Richard Pazdur, M.D., said during Friday’s meeting.

In this model, rather than abandoning the drug altogether, a company can keep the trial going for long-term readouts despite intermediate endpoint failure.

“This is one of the things that we are cautioning people about repeatedly, is not to put all of their eggs in one basket, as far as this […] genuflecting in front of this altar of response rate,” Pazdur said.

In another uncertainty, there doesn’t seem to be enough knowledge about what level of improvement in MRD negativity can be considered efficacious. The i2TEAMM’s analysis found that trials that produced a 40% reduction or more in the risk of progression or death all featured a 20% or higher improvement in MRD negativity.

The FDA admitted that it doesn’t have as clear an efficacy bar for MRD as it did with overall response rate. Before more analyses are available, the FDA will decide on each application on a case-by-case basis, one FDA official said.

“If we need more experience with it, you’d be taking a look at the total body of evidence that would come in,” Pazdur said.

Public comment debate

During the public comment period of the mostly—and unusually—cordial advisory commission meeting, Vinay Prasad, M.D., a hematologist oncologist from the University of California San Francisco, voiced vehement opposition to using MRD to support accelerated approvals.

He argued that, because first-line myeloma patients can already live for a median 10 years, there is no unmet need to pursue a separate accelerated approval pathway. What’s more, an early nod may bring additional safety issues that wouldn't be captured at the time of MRD analysis. He raised the situation where the side effect of Parkinsonism was observed in myeloma CAR-T therapies about seven years after their first tests in humans.

The FDA and the advisory committee members all highlighted the importance of safeguarding patient safety, pointing to the FDA’s responsibility and authority to withdraw a drug later on if clinical benefit was not verified.

Michael Riotto, a patient representative on the advisory panel, fought back at the opposition.

“I’ll be honest with you, it really annoyed me when he said, ‘well, you’ve got 15 years,’” Riotto said. “I want to live 50 years or 60 years or 70 years. And have an MRD negativity […] if it can bring a drug to market faster, as an educated patient, I’ll take that risk. That’s what clinical trials are all about.”

As the FDA looks on track to adopt MRD as a surrogate endpoint in myeloma, Sanofi could be one of the first companies to benefit. A phase 3 trial dubbed IsKia, which uses MRD as the primary endpoint, recently showed that a combination of Sanofi’s Sarclisa, Amgen’s Kyprolis, Bristol Myers Squibb’s Revlimid and dexamethasone (KRd) was significantly better than KRd alone at improving MRD negativity rate in first-line myeloma patients. PFS and OS are the trial’s secondary endpoints.

Sanofi is encouraged by the IsKia data and is “committed to exploring every option to support patients with multiple myeloma,” the company told Fierce Pharma a few days ahead of the Friday meeting.