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. 

The FDA's Oncologic Drugs Advisory Committee (ODAC) met on Tuesday to discuss a pair of regulatory applications from Roche and Johnson & Johnson. While J&J's data package for Darzalex Faspro (daratumumab and hyaluronidase-fihj) got a vote of confidence as a treatment for high-risk smoldering multiple myeloma (HR-SMM), the expert panel was concerned about regional disparities in the supporting data for Roche's CD20xCD3 bispecific antibody Columvi (glofitamab-gxbm) to treat relapsed or refractory diffuse large B-cell lymphoma (DLBCL).'Inconsistent results' for ColumviIn 2023, the FDA granted accelerated approval for Columvi to treat third-line DLBCL, based on response-rate data from a Phase I/II trial. Roche has been running the Phase III STARGLO trial as a confirmatory study to win full approval of the bispecific, as well as to support a supplementary application to move it into earlier treatment settings. At the European Hematology Association (EHA) meeting last June, Roche reported results from 274 patients with second-line DLBCL enrolled in STARGLO showing that those who received a combination of Columvi plus gemcitabine and oxaliplatin (GemOx) experienced a statistically significant 41% reduction in the risk of death. Additionally, the regimen also led to   a median overall survival (OS) of 25.5 months versus 12.9 months for the comparator arm, as well as a significant improvement in progression-free survival (PFS) of 63%. At the time, researchers noted that Columvi "is the first CD20xCD3 bispecific antibody to demonstrate survival benefit in DLBCL in a randomised Phase III trial."Roche has since filed global applications seeking approval of Columvi in combination with GemOx to treat patients with relapsed or refractory DLBCL who are not candidates for autologous stem cell transplant — and in April, was granted the broader label by EU regulators.European physicians are already excited about Columvi, with 94% respondents to a recent FirstWord poll reporting that the bispecific's efficacy profile is somewhat or significantly better than existing second-line options (see – Physician Views Results: Roche's Columvi looks well placed to take on CAR-T in second-line lymphoma patients).However, Roche's chances to move Columvi into the second-line DLBCL setting in the US are looking slim after ODAC took issue with what briefing documents compiled by FDA staff called "inconsistent results… regarding the robustness of the efficacy and safety data." According to an agency report shared ahead of Tuesday's meeting, there were notable differences in OS, PFS, overall response rate and complete response rate "based on race and region, with the results being largely driven by outcomes in the Asian region." In STARGLO, about 131 patients were from an Asian region, while 143 were not — including 25 Americans, or 9% of the total trial population. While Columvi's benefit "was clearly demonstrated in patients enrolled in the Asian countries…the treatment effect was substantially less and potentially worse for those patients enrolled in the Non-Asian countries," according to the briefing documents. "The FDA is concerned by the lack of internal consistency observed in the STARGLO trial and how the results of the Asian region appear to be driving the overall trial results."While ODAC was not asked to make a recommendation on Roche's supplementary filing for Columvi, the panelists seemed to agree with the FDA's concerns regarding the data, voting 8 to 1 that STARGLO's population and trial results are not applicable to the proposed US patient population. Roche and its Genentech unit refuted that conclusion in a company release Tuesday. "The clinical and disease characteristics of the overall population enrolled in this multiregional clinical trial are representative of US patients with this disease today," according to Genentech. "Based on extensive guidelines and real-world clinical practice, there are no biological or clinical differences for DLBCL management worldwide."Darzalex passes scrutinyJ&J fared better during its turn in the hot seat on Tuesday. ODAC voted 6-2 that Darzalex has a favourable risk-benefit profile to treat adults with HR-SMM, an asymptomatic, premalignant stage of the disease typically diagnosed during routine bloodwork or investigations for unrelated issues. Current practice is to monitor patients every three to six months, with interventional treatment not initiated unless progression to symptomatic disease is observed (see – Spotlight On: AdCom intrigue — Will Darzalex discussion showcase new FDA attitudes?).The panel's positive vote was based on data from the Phase III AQUILA study, which were presented at the American Society of Hematology (ASH) meeting in December. After a median follow-up of 65.2 months, Darzalex led to a 60-month PFS rate of 63.1% and a five-year OS rate of 93% versus 40.8% and 86.9%, respectively, in the active monitoring group.The consensus among a dozen world-leading MM experts recently interviewed by FirstWord for a forthcoming Therapy Trends report is that data from AQUILA is sufficient to secure approval of Darzalex. Key opinion leaders note that the demonstration of an OS advantage, whilst small, is the key piece of data in establishing Darzalex’s viability in treating smouldering MM, and has renewed interest in treating this condition.The vote in favour of Darzalex was not guaranteed however — exemplified by the two dissenting nays — as an FDA report suggested that the anti-CD38 antibody has an uncertain benefit-risk profile. The agency noted that AQUILA's endpoints "are of uncertain clinical meaningfulness in smouldering MM," adding that "while the trial met its primary PFS endpoint there is uncertainty in the benefit of delaying progression to MM in the absence of a significant improvement in OS."Additionally, the absence of a standardised definition to identify HR-SMM could mean a lack of consistency in how patients are treated (see – KOL Views Q&A: Darzalex data intrigue but are not a home run in smouldering myeloma).