Carvykti outperforms standard care as earlier line of therapy: Analysis
Phase 3 clinical trial tested drug against 2 common combination treatments
Carvykti (ciltacabtagene autoleucel) significantly reduces the risk of disease progression or death in adults with multiple myeloma who received one to three prior lines of therapy and failed to respond to standard Revlimid (lenalidomide).
That’s according to the first data analysis, at nearly 1.5 years of follow-up, of the ongoing Phase 3 CARTITUDE-4 clinical trial (NCT04181827), which is testing Carvykti against two commonly used combination treatments.
Results were recently presented at the 2023 American Society of Clinical Oncology Annual Meeting held June 2-6 in Chicago and virtually, and published in The New England Journal of Medicine, in the study “Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma.” The work was funded by Carvykti’s co-developers Legend Biotech and Janssen.
“Data from CARTITUDE-4 demonstrated strong results for study patients after first relapse,” Mythili Koneru, MD, PhD, Legend Biotech’s chief medical officer, said in a company press release. “We are inspired by the potential of [Carvykti] for patients with multiple myeloma who continue to have a high need for another treatment option.”
Seeking expansion of Carvykti’s current label in Europe
Based on these data, Janssen has filed an application to authorities in Europe seeking an expansion of Carvykti’s current label to also cover adults with relapsed and Revlimid-resistant multiple myeloma.
Carvykti was conditionally approved by the European Commission last year to treat adults with relapsed or refractory multiple myeloma (RRMM) who had failed to respond to at least three prior lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and a CD38 inhibitor.
“The previous European Commission approval recognised the potential for [Carvykti] to positively impact outcomes for people living with relapsed and refractory multiple myeloma. Today’s submission … is an important step towards helping patients benefit from this CAR-T therapy earlier in their treatment journey,” Edmond Chan, MD, senior director, EMEA therapeutic area lead hematology at Janssen-Cilag Limited, said in a company press release.
In the U.S., Carvykti is approved for RRMM adult patients who have received at least four prior lines of therapy, including those same three therapy classes.
Carvykti, also called cilta-cel, is a cell therapy that involves collecting a patient’s immune T-cells, equipping them with a chimeric antigen receptor (CAR) that helps them target and kill myeloma cells, and then infusing them back into the patient.
If authorities in Europe approve the label expansion, Carvykti “will be the first and only CAR-T therapy available to treat relapsed and refractory multiple myeloma patients as early as second line,” Chan said.
Revlimid is an IMiD commonly used as early-line treatment for multiple myeloma. However, “the frequency of [Revlimid] resistance early in the treatment journey is increasing, which has led to a growing need for new, effective therapies for [Revlimid-refractory] disease,” the researchers wrote.
Global study CARTITUDE-4 enrolled 419 adults
CARTITUDE-4 (NCT04181827) is the first appropriately controlled Phase 3 clinical trial “investigating the efficacy of a cell therapy versus standard of care … as early as after first relapse in [Revlimid-refractory] multiple myeloma,” Legend Biotech stated in the release.
The global study enrolled 419 adults with myeloma who had failed to respond to Revlimid and up to two other therapies, including PIs and IMiDs. Participants were randomly assigned to receive either a single dose of Carvykti or standard-of-care treatment and are being followed for up to six years.
Standard treatment included the IMiD Pomalyst (pomalidomide) combined with the PI Velcade (bortezomib) and dexamethasone or the CD38 inhibitor Darzalex (daratumumab) combined with Pomalyst and dexamethasone.
Results, at a median of about 16 months of follow-up, showed the risk of disease progression or death was significantly lower, by 74%, in patients given Carvykti compared with standard care.
Specifically, median progression-free survival, or the time a person lives without signs of disease progression, was about one year for patients on standard treatment, but was not reached in the Carvykti group. This means that more than half of patients given the cell therapy had not experienced disease progression at the latest follow-up.
The cell therapy also was associated with a 65% reduction in the risk of disease progression or death among patients who had received only one prior line of therapy.
At one year, less than a quarter (24.1%) of Carvykti-treated patients had experienced disease progression, compared with slightly more than half (51.4%) of those on standard treatment.
Higher response rates in Carvykti group
Response rates were higher in the Carvykti group than among patients with standard care (84.6% vs. 67.3%). Also, patients on the cell therapy were more than three times more likely to show complete or better responses (73.1% vs. 21.8%) and about four times more likely to have no detectable cancer cells on follow-up tests (60.6% vs. 15.6%).
“The strong progression-free survival benefit and rapid and deep response with [Carvykti] highlight the potential for [Carvykti] to become a therapeutic option for patients with myeloma after the first relapse,” the researchers wrote.
Severe or life-threatening adverse events were reported in virtually all trial participants, with the most common being low blood cell counts and infections. Rates of these events were generally comparable between the two patient groups.
Most Carvykti-treated patients (76.1%) developed cytokine release syndrome (CRS), a potentially life-threatening complication, and 4.5% experienced an inflammation-associated neurological disorder called immune effector cell-associated neurotoxicity syndrome. These side effects, which are known to occur with CAR T-cell therapies like Carvykti, were generally judged as mild to moderate in severity.
“Overall, CAR-T–specific adverse events were manageable with appropriate supportive care,” the researchers wrote.
A total of 39 Carvykti-treated patients and 46 of those on standard care died. Among these, 10 deaths in the Carvykti group and five in the standard group were judged as related to adverse events, while deaths from myeloma progression occurred in 14 patients on Carvykti and 30 on standard care.
The cause of death of 7 of the 10 Carvykti-treated patients who died due to adverse events was COVID-19 infection, which developed within four months after the therapy was infused, when patients’ immune systems were weakened.
“These deaths contributed to the higher number of fatal events observed in the [Carvykti] group than in the standard-care group in the first year … and highlight the need for strict prevention measures and aggressive treatment of Covid-19 in patients receiving CAR-T therapies,” the researchers wrote, noting that no COVID-19-related deaths were reported after stricter safety guidelines were put in place.
Overall, these data show “a favorable risk–benefit profile for a single infusion of [Carvykti] as compared with standard care,” the researchers concluded.
They noted a limitation of the study was that the standard-of-care treatment options did not include some medicines that have recently been approved, so it’s not possible to say how Carvykti might stack up against these newer therapies. The team also noted that work is ongoing to understand why a minority of patients don’t respond to Carvykti.
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