Key takeaways:
- The panel voted in opposition to using two separate belantamab mafodotin regimens for sure sufferers with a number of myeloma.
- Committee members voiced issues over proposed dosages and threat for ocular toxicity.
An FDA advisory committee dominated in two separate votes that two belantamab mafodotin mixture regimens shouldn’t be used within the proposed dosages for beforehand handled grownup sufferers with relapsed/refractory a number of myeloma.
The FDA Oncologic Medicine Advisory Committee (ODAC) voted 5-3 in opposition to belantamab mafodotin (Blenrep, GSK) dosed at 2.5 mg/kg each 3 weeks together with bortezomib (Velcade, Takeda) and dexamethasone.
The ODAC voted in opposition to two separate belantamab mafodotin regimens for sure sufferers with multi-ple myeloma.
The committee moreover voted 7-1 in opposition to an preliminary cycle of belantamab mafodotin dosed at 2.5 mg/kg, adopted by 1.9 mg/kg each 4 weeks, together with pomalidomide (Pomalyst, Celgene) and dexamethasone.
The FDA accepted the biologics license utility for the at the moment proposed belantamab mafodotin regimens in November 2024, primarily based on findings from the section 3 DREAMM-7 and DREAMM-8 trials. Each trials met their major endpoints of PFS, however DREAMM-7 additionally demonstrated statistically vital enchancment in OS.
Nevertheless, researchers noticed constant ocular opposed occasions in each trials, reported by 79% of sufferers assigned the belantamab mafodotin routine vs. 29% within the management group in DREAMM-7, and 89% of sufferers who acquired the belantamab mafodotin routine vs. solely 30% amongst controls in DREAMM-8.
A number of members of ODAC defined the reasoning for his or her votes, citing issues over ocular toxicity on the really helpful doses.
“This was a difficult resolution as a result of the efficacy knowledge had been robust, however the toxicity knowledge had been additionally very robust,” Neil Vasan, MD, PhD, assistant professor within the division of hematology and oncology at Herbert Irving Complete Most cancers Heart at Columbia College, mentioned in the course of the assembly.
“I’d like to emphasise the phrases ‘on the proposed dosage.’ This was, for me, what swayed the choice,” he added. “This was a missed alternative over the course of a few years of growth of this drug to discover these totally different dosages.”
Further issues voiced by committee members included the low variety of U.S.-based sufferers included in each trials.
“It isn’t my place to say whether or not this shall be authorized by the FDA, so I’m simply voting primarily based on the verbiage within the query and it particularly states ‘within the proposed affected person inhabitants,’” Daniel Spratt, MD, professor and chair of the division of radiation oncology at Case Western Reserve College, mentioned in the course of the assembly. “That is the US FDA, so the proposed affected person inhabitants is United States sufferers. The medical growth program enrolled nearly no sufferers in the US, so it precludes any evaluation of the benefit-risk profile within the U.S.”
Saad Z. Usmani, MD, MBA, FACP, FASCO, myeloma specialist and mobile therapist at Memorial Sloan Kettering Most cancers Heart, and a Healio | HemOnc Right this moment Editorial Board member, spoke in assist of the agent.
Saad Z. Usmani
“I used to be shocked by how the voting turned out, which can be a results of the wording of the query for each regimens posed to the ODAC panel,” Usmani advised Healio. “Nevertheless, I stay hopeful that the DREAMM-7 and DREAMM-8 trials will result in an FDA approval within the close to future to assist extra sufferers within the U.S. which may not produce other choices at their disposal like CAR-T — particularly for Individuals in rural settings.
“It’s actually shocking to see a examine that met its major endpoint — one of many research even exhibits a secondary endpoint of OS — nonetheless obtain a detrimental ODAC listening to,” Usmani continued. “This doesn’t essentially imply that the FDA might not approve the remedy, however with caveats.
Usmani mentioned he’s hopeful that FDA regulatory advisors will make the proper resolution.
“These are a few of the finest PFS knowledge that we’ve got on this line of remedy, so it’s a bit disappointing that the dialogue began to concentrate on the reversible eyesight unintended effects, which we knew about for five or 6 years now,” he mentioned. “I’m hopeful that the regulatory advisors will make the proper resolution, as a result of entry to [certain CAR-T therapies] is proscribed.
“There are gaping entry to care deserts within the U.S., particularly in center America, the place for miles and miles we don’t have a mobile remedy transplant heart in neighborhood practices that might profit from off-the-shelf [B cell maturation antigen]-directed choices.”
For extra info:
Saad Z. Usmani, MD, MBA, FACP, FASCO, might be reached at usmanis@mskcc.org.
Perspective
I recognize the troublesome questions the ODAC members had been navigating, since they had been particularly requested to vote on the benefit-risk ratio of belantamab mafodotin on the actual dosing schedules studied in DREAMM-7 and DREAMM-8. I’ll admit that many people within the subject had been shocked by what number of members voted “no” regardless of an OS profit lately proven in DREAMM-7.
Nobody within the subject would disagree that belantamab mafodotin dosing shall be optimized in coming years. A number of myeloma is the most typical malignancy, the place for a wide range of causes — together with its incurable nature and lengthy follow-up wanted for trials — trendy drug-dosing paradigms routinely are nearly all the time decrease than the unique trial-studied schemas.
Bortezomib is dosed directly weekly vs. twice weekly, bispecific antibodies are de-escalated to each 4 to eight weeks somewhat than weekly and selinexor (Xpovio, Karyopharm Therapeutics) is usually dosed at lower than half of its authorized dose listed within the U.S. bundle insert.
I stay cautiously optimistic that the total FDA should approve these belantamab mafodotin mixtures primarily based on their profound PFS advantages in section 3 trials. There are lots of sufferers throughout the U.S., together with a couple of in my private observe, who aren’t candidates for B-cell maturation antigen-targeted bispecific antibodies or CAR-T therapies. For these sufferers, belantamab mafodotin will work fairly effectively. We already know that belantamab mafodotin dose de-escalations protect efficacy and may help ocular toxicities resolve utterly.
To the extent that the ODAC members concluded that the optimum dosing schedule for belantamab mafodotin was decrease than the exact schemas studied in DREAMM-7 and DREAMM-8, I utterly agree. Nevertheless, I nonetheless hope that FDA approval will permit us to gather real-world proof to assist us discover the most effective methods to dose this vital drug for real-world sufferers.
Rahul Banerjee, MD, FACP
Fred Hutchinson Most cancers Heart
College of Washington
Disclosures: Banerjee reviews consulting and/or analysis for AbbVie, Adaptive Biotech, Bristol Myers Squibb, Caribou Biosciences, Genentech, GSK, Janssen, Johnson & Johnson, Karyopharm, Legend Biotech, Novartis, Pack Well being, Pfizer, Prothena, Sanofi and SparkCures.
Perspective
Belantamab mafodotin was withdrawn from the market attributable to failure of a confirmatory trial. The ODAC was held to debate two current section 3 trials that in contrast a combination-based triplet, together with belantamab mafodotin, within the earlier relapse setting. The main concern of using belantamab mafodotin is the distinctive opposed occasions with ocular toxicity that will lead to worsening high quality of life, in addition to lack of probably the most acceptable dosing schema for that drug.
The speed of drug modification/dose delay was considerably greater than different myeloma remedies, which is regarding since this may increasingly point out that the dosing schema just isn’t what might be tolerated with sufferers. There are some medical trials which might be investigating a decrease dose and fewer frequent dosing that may assist to higher deal with this. It’s famous that deep responses are decrease with a decrease dose/much less frequent dosing from prior research. It will likely be vital to seek out the dose that works finest whereas avoiding the excessive charges of drug delays and discontinuations.
One vital factor to spotlight is the visible acuity modifications, with roughly 30% having 20/100 visible modifications or worse. This resulted in roughly 40% of sufferers reporting that they can not drive at night time and that they’ve modifications in each day actions. A few of these modifications lasted for a month and recurred with future dosing.
Sufferers might want to have common eye checks with an ophthalmologist or optometrist, and this might not be accessible to everybody.
We’re in a brand new period with a number of B-cell maturation antigen-based therapies authorized at numerous illness phases. Whereas some sufferers benefited with using belantamab mafodotin when it was the one B-cell maturation antigen-directed remedy, it’s unclear if it will likely be of comparable profit now.
One huge suggestions to all of us is to look at a number of doses and attempt to optimize the most effective dose earlier than continuing with massive medical trials.
Samer Al Hadidi, MD, MS, FACP
College of Arkansas Medical Sciences
Disclosures: Al Hadidi reviews receiving consulting charges from Janssen and Sanofi, in addition to analysis assist from Alexion, Janssen, Pfizer and Worldwide Myeloma Society.
