If a new package of pivotal data satisfies the FDA, GSK could have another run at the U.S. multiple myeloma market with its previously withdrawn BMCA-targeted antibody-drug conjugate, Blenrep.
GSK telegraphed the latest phase 3 win in a surprise announcement in November, a year after the company pulled Blenrep as a monotherapy for heavily pretreated multiple myeloma patients in the U.S. Now, detailed data show the promise of Blenrep as a second-line treatment as part of a combination regimen.
The combination of Blenrep with Takeda’s Velcade and the steroid dexamethasone (Vd) significantly cut the risk of progression or death by 59% compared with Johnson & Johnson’s Darzalex and Vd in patients who had tried at least one prior line of therapy. The data, from the phase 3 DREAMM-7 trial, will be presented at the American Society of Clinical Oncology plenary series this week.
Perhaps more importantly, although the result is immature, the Blenrep regimen cut the risk of death by 43% at the interim analysis. The preliminary showing just narrowly missed statistical significance at this point, and the trial is progressing to its next survival analysis.
The readout comes in contrast to that from the DREAMM-3 trial, in which Blenrep alone failed to significantly prolong progression-free survival compared with the combination of Bristol Myers Squibb’s Pomalyst and dexamethasone (Pd) in previously treated patients. That confirmatory trial flop led to the withdrawal of Blenrep’s accelerated approval as a late-line therapy.
On Monday, GSK’s global head of oncology R&D, Hesham Abdullah, M.D., declined to comment on the British pharma’s regulatory plan. Another phase 3 trial, DREAMM-8, is testing Blenrep plus Pd against the combination of Pomalyst, Velcade and dexamethasone (PVd), also in the second-line setting. DREAMM-8 is expected to read out in the second half of this year.
That trial is basically evaluating Blenrep head-to-head with Velcade, while the current DREAMM-7 study is really pitting Blenrep against Darzalex.
Having data from two studies that basically go head-to-head against existing treatments is important, Abdullah said. “Both studies are going to be very meaningful when we look at the data in aggregate,” he said of DREAMM-7 and -8.
“One of the most powerful ways to help not only characterize the treatment effect, but to really be able to demonstrate the efficacy of a drug, is to provide independent replicability of treatment effect from two studies,” Abdullah said.
GSK will likely need two independent wins to change doctors’—and investors’—views of Blenrep after the monotherapy fail.
The DREAMM-7 readout naturally invites a cross-trial comparison with the results for J&J and Legend Biotech’s star BCMA CAR-T therapy Carvykti from the CARTITUDE-4 trial, also in the second-line-plus setting.
In CARTITUDE-4, Carvykti slashed the risk of disease progression or death by a whopping 74% against a standard treatment combo in patients who had tried one to three prior lines of treatment. At face value, Carvykti’s magnitude of progression-free survival improvement is much bigger than Blenrep’s 59%. But there are several differences between the two trials.
Patients in the control arm of DREAMM-7 received the Darzalex-Vd combo, whereas control patients in CARTITUDE-4 got Darzalex-Pd or PVd. Baseline patient characteristics, such as the number of patients for each line of treatment and high-risk factors, could also contribute to the variability, Abdullah noted.
In the Carvykti trial, patients in the control arm went a median 11.8 months without disease progression. In DREAMM-7, the median PFS for the control group was 13.4 months, versus 36.6 months for the Blenrep arm. The median PFS for Carvykti was not reached at a previous data release in June after a median follow-up of 15.9 months.
Blenrep comes as a more convenient readily available treatment, whereas Carvykti, as a CAR-T, requires a long preparation process. Blenrep can be given in a community setting, but J&J and Legend are also pushing for increased outpatient administration of Carvykti thanks to the drug's unique side-effect profile.
For now, Blenrep’s preliminary 43% death-risk reduction looks very encouraging, and Abdullah said he likes the shape of the drug’s patient survival curve and where it’s headed. Investigators will present the overall survival line chart during the ASCO plenary session Tuesday.
By comparison, Caryvkti showed a preliminary 22% reduction in the risk of death. In a concerning sign for the J&J and Legend drug, the FDA has scheduled an advisory committee meeting to discuss CARTITUDE-4’s overall survival data, which will likely include an updated analysis.
For Blenrep’s potential revival, the DREAMM-7 and -8 readouts are a starting point, Abdullah said. GSK is evaluating various development strategies for Blenrep in different lines of therapies. Beating Darzalex in DREAMM-7 bodes well for the BCMA ADC, given that combinations based on the CD38 agent are becoming the standard of care in newly diagnosed patients, the GSK exec said.
The DREAMM-7 win “certainly gives you some pause and reflection to say, Blenrep was able to beat [Darzalex]-based regimen head-to-head,” Abdullah said. “You do wonder about what could happen in different lines of therapy.”
Going into the first line won’t be easy. Besides a high efficacy bar, safety is also a key consideration and could become an obstacle for the GSK drug. Blenrep is known to come with an increased risk of eye toxicity. In DREAMM-7, grade 3 or higher ocular adverse events happened in 34% of patients who received Blenrep.
But Abdullah stressed that the problem is manageable, and GSK has a clear strategy to mitigate and reverse the side effects. All told, eye-related side effects led to a 9% rate of treatment discontinuations.