Daratumumab/Hyaluronidase-fihj

The FDA’s Oncologic Drugs Advisory Committee voted 6 to 2 in favor of the benefit-risk profile of Darzalex Faspro to treat patients with high-risk smoldering multiple myeloma. Johnson & Johnson has won the support of an FDA expert panel in its bid to make Darzalex the first treatment for an early form of multiple myeloma despite uncertainties raised by regulators.The FDA’s Oncologic Drugs Advisory Committee voted 6 to 2 in favor of the benefit-risk profile of Darzalex Faspro to treat patients with high-risk smoldering multiple myeloma (SMM), an asymptomatic precursor condition to active myeloma.As no treatments are currently approved specifically for SMM, the subcutaneous formulation of Darzalex could become the first therapy in the indication. The FDA doesn’t have to follow the recommendations of its expert panels, but it typically does.During Tuesday’s committee meeting, the FDA raised various questions about whether active treatment with Darzalex in this early-stage disease is appropriate based on data from J&J’s phase 3 Aquila trial, which evaluated the drug against simple monitoring in high-risk SMM. Eventually, consistent favorable findings across multiple analyses, including an early trend suggesting Darzalex Faspro could extend patients’ lives, persuaded most panelists.“My vote comes down to all the endpoints effectively are favoring the intervention here,” Dan Spratt, M.D., from Case Western Reserve University, said after voting in support of Darzalex.However, J&J’s development and regulatory experience highlights the increased difficulties drugmakers are facing when running clinical trials in early-stage cancers, including identifying the right patients who can benefit the most from treatment intensification.“I think this is going to be a broader issue across all of oncology," Ravi Madan, M.D., from the National Cancer Institute, said in explaining his “no” vote against Darzalex. "We’re getting better technology every day. We’re getting more opportunities to treat earlier. And I think again, we have to really step back and ask ourselves, just because we can treat earlier, should we?”The FDA, for its part, focused its questioning mainly on three arguments. For one, the Aquila trial enrolled more than half of its patients who did not fit the current high-risk criteria, the FDA noted. In addition, even though the trial met its primary endpoint of progression-free survival—defined as progression to active multiple myeloma or death—the clinical meaningfulness of the drug’s efficacy is unclear without “appreciable” improvement on the time to progression while on a later-line therapy and without overall survival evidence, the FDA argued.Third, the risks related to any potential impact of early SMM treatment with Darzalex on future multiple myeloma treatment, as well as the drug’s toxicities in this indication, may be too burdensome to warrant treatment, the FDA contended. On the first point, the high-risk standards have been updated after Aquila’s initiation in 2017. As a result, only 41% of trial participants fit the new high-risk definition.But the fact that half of the patients in the active monitoring arm progressed to multiple myeloma by three years showed that this was indeed a high-risk group of patients, Vincent Rajkumar, M.D., from the Mayo Clinic, who participated in setting SMM risk characterization standards, said during J&J’s presentation.“When people ask me, 'what is high-risk smoldering myeloma,' we say any criteria that gets you that 40%, 50% risk at two or three years is the high-risk group,” he said. “What we’re trying to do is every criteria misses some of the patients who will progress in the first two or three years […] The stricter you make the criteria, the more people you will miss.”As for the second issue, subcutaneous Darzalex reduced the risk of SMM progressing to active multiple myeloma by 51% versus surveillance. However, the FDA doubted whether simply delaying progression is enough given that almost all SMM will eventually become active myeloma. The FDA’s reviewers suggested that progression-free survival 2 (PFS2), which assesses the time between randomization to disease progression on first-line multiple myeloma treatment, and eventually overall survival, may help assess an SMM therapy’s efficacy.Among patients who match the updated high-risk definition, Darzalex’s benefit on PFS2 was just 9%, according to an FDA subgroup analysis.On overall survival, the FDA was not convinced by a six-percentage-point difference between the two trial arms at five years. The Aquila trial was not sufficiently powered to show a significant survival benefit, and it may not be realistic to request that evidence at this stage, the FDA noted.But Spratt pushed back on the FDA’s perception that the survival improvement shown so far was not meaningful. For an indolent disease, “that’s pretty profound,” he said. Additionally, the FDA was worried that the Aquila trial didn’t provide sufficient data on the effect of treatment in the smoldering state on a patient’s ability to respond to Darzalex or similar anti-CD38 regimens that are known to provide benefit in multiple myeloma.Only a small proportion of Aquila patients used Darzalex-containing first-line therapy after developing multiple myeloma, and neither J&J nor the FDA performed a PFS or survival analysis in those patients because the number of cases was too small.Still, all patients in the Darzalex arm who received a CD38-containing follow-on regimen—including Sanofi’s Sarclisa—during the active myeloma phase are responding to therapy and still on therapy to date now, a J&J exec noted during Tuesday’s discussion.As to safety, the Darzalex arm experienced higher rate of treatment-emergent adverse events. In response, J&J cited a patient-reported outcomes assessment showing similar results between treatment arms. However, the FDA said it couldn’t rely on that J&J data set because the assessments of patients were inadequate.Despite the toxicities, Mark Conaway, Ph.D., from the University of Virginia, said he saw “a sizable portion of a population whose perception of benefit would outweigh the risk” with Darzalex.Nevertheless, several members of the committee called for careful definition of the eligible patient population in a potential FDA approval and for continued follow-up of the Aquila trial to further understand Darzalex’s profile in this groundbreaking indication.