Updated re­­sults of a Phase 1 trial testing bb2121 in re­lapsed mul­ti­ple myeloma patients were pre­sented last Friday at the American Society of Clinical Oncology (ASCO) annual meeting. bb2121 is a poten­tial new myeloma treat­ment in the chi­meric an­ti­gen re­cep­tor (CAR) T-cell class of ther­a­pies.

The re­­sults pre­sented at this year's ASCO meeting con­firm pre­vi­ous findings in­di­cating bb2121 has sub­stan­tial anti-myeloma ac­­tiv­ity.

At some of the higher doses of bb2121 tested during the trial, for example, nearly every patient treated with the drug responded to it; the over­all re­sponse rate was almost 100 per­cent.

For a single drug to achieve a re­sponse rate of almost 100 per­cent in any myeloma patient pop­u­la­tion is a sig­nif­i­cant achieve­ment. In newly myeloma diag­nosed patients, for example, it takes a three-drug regi­men, such as Revlimid (lena­lido­mide), Velcade (bor­tez­o­mib), and dexa­meth­a­sone, to achieve close to a 100 per­cent over­all re­sponse rate.

The patients in the bb2121 trial, how­ever, were not newly diag­nosed. They were heavily pre­treated and there­fore much less likely to respond to treat­ment than newly diag­nosed patients. Trial par­tic­i­pants pre­vi­ously had been treated with Revlimid, Velcade, Pomalyst (poma­lido­mide, Imnovid), Darzalex (dara­tu­mu­mab), and Kyprolis (car­filz­o­mib) at one point or another. Yet the over­all re­sponse rate to bb2121 treat­ment was 95.5 per­cent in trial par­tic­i­pants treated with higher doses of the drug.

The re­sponses to bb2121 were also deep re­sponses. Every patient who responded to treat­ment and underwent testing for the presence of minimal residual dis­ease (MRD) was found to be MRD neg­a­tive, meaning no signs of myeloma could be found in the patient’s bone mar­row cells. These patients had a median pro­gres­sion-free sur­vival of 17.7 months.

Across all patients who re­ceived what the re­searchers char­ac­ter­ized as “active” doses of bb2121, the median pro­gres­sion-free sur­vival was 11.8 months.

If there was any disappointment with the bb2121 re­­sults, it was that that the pro­gres­sion-free sur­vival re­­sults were not even longer than they were. Some had hoped that there might be signs in this trial that bb2121 can be curative in some patients. That is not yet the case, although such a re­sponse could be seen when bb2121 is tested in the future in patients who have not yet undergone many prior ther­a­pies.

Dr. Noopur Raje of Massachusetts General Hospital in Boston pre­sented the bb2121 re­­sults last Friday. She described bb2121’s safety profile in the trial as man­ageable, although a fair num­ber of patients ex­peri­enced cytokine re­lease syn­drome, a con­di­tion where inflam­ma­tion and symp­toms of in­fec­tion oc­cur without any infectious cause.

The U.S. pharma­ceu­tical com­pany Celgene, which mar­kets the myeloma drugs thalido­mide, Revlimid, and Pomalyst, is devel­op­ing bb2121 in col­lab­o­ra­tion with the bio­technology com­pany bluebird bio.

The U. S. Food and Drug Admin­istra­tion granted bb2121 break­­through ther­apy desig­na­tion in No­vem­ber 2017 (see re­lated press re­lease ^[6]), and bluebird says it ex­pec­ts to file appli­ca­tions in 2019 with U.S. and Euro­pean author­i­ties for poten­tial ap­prov­al of bb2121 as a new myeloma ther­apy. Such ap­prov­als, if granted, would prob­a­bly come in 2020.

CAR T-Cell Therapy

Chimeric an­ti­gen re­cep­tor (CAR) T-cell ther­apy belongs to a broader class of cancer ther­a­pies known as immuno­therapies, which seek to use the body's im­mune sys­tem to fight cancer. CAR T-cell ther­apy also belongs to a class of treat­ments known as adoptive cel­lu­lar ther­a­pies, which focus on using altered T cells to treat dis­eases.

T cells are a type of white blood cell that attack and kill viruses and cancer cells. Cancers that are able to take hold in the body, how­ever, have devel­oped ways of making it hard for T cells to suc­cess­fully attack them. One way they accomplish this is by making it dif­fi­cult for the T cells to recog­nize them as cancer cells.

In CAR T-cell ther­apy, a cancer patient’s T cells are harvested and then ge­net­ic­ally altered so that they are better able to identify and attack the patient’s spe­cif­ic type of cancer, such as a mul­ti­ple myeloma. The altered T cells are then stim­u­lated to reproduce so that a large num­ber of the altered cells can be re-infused back into the patient’s body to (hopefully) treat the patient’s cancer.

The way the T cells are altered to better identify and attack a spe­cif­ic cancer is by modifying them so that they are attracted to a pro­tein found on the surface of the cancer cells. In the case of bb2121, for example, the T cells are altered so they are attracted to cells with a surface pro­tein known as B cell maturation an­ti­gen (BCMA). Previous re­search has shown that BCMA en­cour­ages many processes that enable myeloma cell growth, sur­vival, and pro­lif­er­a­tion (see re­lated Beacon ^[7] news).

Design Of The bb2121 Phase 1 Clinical Trial

There were two parts to the Phase 1 “CRB-401” trial for bb2121 whose re­­sults were pre­sented by Dr. Raje last Friday.

The first “dose escalation” part of the trial was focused on estab­lish­ing the safety and appro­pri­ate dose of bb2121.

In the sec­ond “dose ex­pan­sion” part of the trial, the range of tested doses was narrowed to those most likely to be active, and there was a greater focus on assessing the ef­fi­cacy of the drug.

The re­­sults pre­sented last Friday are based on data from 43 patients who took part in either part of the trial. All patients had late-stage re­lapsed and re­frac­tory mul­ti­ple myeloma. Of those, 21 were part of the dose escalation part of the trial, and 22 in the dose ex­pan­sion part of the trial.

Patients in both parts of the trial were heavily pre­treated. Those in the dose escalation part of the trial had re­ceived a median of seven prior ther­a­pies, and those in the dose ex­pan­sion part of the trial had re­ceived eight prior ther­a­pies. Almost all patients had pre­vi­ously re­ceived a stem cell trans­plant and treat­ment with Velcade, Kyprolis, Revlimid, Pomalyst, and Darzalex at some point.

In the dose escalation part of the trial, patients re­ceived one of four bb2121 dose levels (50, 150, 450, or 800 mil­lion cells).

In the ex­pan­sion part of the trial, study par­tic­i­pants re­ceived bb2121 doses from 150 mil­lion to 450 mil­lion cells.

Prior to their CAR T-cell in­fusions, patients re­ceived a con­di­tioning regi­men of flu­dar­abine (Fludara) and cyclo­phos­pha­mide (Cytoxan).

Study Results

Efficacy

The up­dated re­­sults pre­sented at ASCO show that almost all patients (95.5 per­cent) who re­ceived bb2121 at dose levels above 150 mil­lion cells in either part of the trial responded to treat­ment, com­pared to 57 per­cent of patients who re­ceived bb2121 at a dose of 150 mil­lion cells, and 33 per­cent of patients who re­ceived the lowest dose (50 mil­lion cells).

During her pre­sen­ta­tion, Dr. Raje used the phrase "active dose" to describe bb2121 doses of 150 mil­lion cells or greater. Using this definition, the re­sponse rate to treat­ment with an active dose of bb2121 was 81 per­cent.

Sixteen patients who responded to treat­ment with bb2121 in either the first or sec­ond part of the trial also have been tested for minimal residual dis­ease. All 16, or 100 per­cent of the patients, were found to be MRD neg­a­tive.

Initial findings in­di­cate that a patient’s re­sponse to bb2121 did not de­pend on how much BCMA, the pro­tein targeted by bb2121, was found on their myeloma cells. Over­all re­sponses rates were similar be­tween patients with low BCMA levels (100 per­cent) and patients with high BCMA levels (91 per­cent).

The median pro­gres­sion-free sur­vival for 18 evaluable patients who got at least an “active dose” (at least 150 mil­lion cells) of bb2121 in the first part of the trial was almost one year (11.8 months).

The longest pro­gres­sion-free sur­vival was seen in the patients in either part of the trial who had achieved MRD neg­a­tive status. The median pro­gres­sion-free sur­vival for these patients was almost a year and a half (17.7 months).

Safety

Overall, 63 per­cent of patients ex­peri­enced cytokine re­lease syn­drome (CRS), a con­di­tion where inflammation and symp­toms of in­fec­tion oc­cur without any infectious cause. The majority of cases were mild to mod­er­ate in nature; only 5 per­cent of the study par­tic­i­pants ex­peri­enced severe CRS, which re­solved within 24 hours. As ex­pec­ted, the share of patients who ex­peri­enced CRS was larger at higher dose levels (82 per­cent at dose levels above 150 mil­lion cells com­pared to 32 per­cent at 150 mil­lion cells).

In addi­tion, one third of patients (33 per­cent) ex­peri­enced neurotoxicity, such as dizzi­ness, drowsiness, in­somnia, confusion, memory im­pair­ment, or tremors.

As for blood-related side effects, severe low white blood cell counts were ob­served in 81 per­cent of patients, and almost two thirds of the patients (61 per­cent) ex­peri­enced severe low platelet counts.

The bb2121 Results In Perspective

The bb2121 ef­fi­cacy re­­sults are impressive for a single drug being used to treat mul­ti­ple myeloma patients who have had many prior ther­a­pies.

Two comparisons involving Darzalex, a drug widely viewed as a very ef­fec­tive myeloma ther­apy, provide perspective on bb2121’s ef­fi­cacy.

In a Phase 2 trial of Darzalex as a single drug used to treat re­lapsed myeloma patients who had a median of 5 prior ther­a­pies, the over­all re­sponse rate was 29 per­cent, and the median pro­gres­sion-free sur­vival was 3.7 months (related journal article ^[8]).

In a Phase 2 trial of the three-drug com­bi­na­tion of Darzalex, Pomalyst, and dexa­meth­a­sone in re­lapsed myeloma patients with a median of 4 prior ther­a­pies, the over­all re­sponse rate was 60 per­cent, and the median pro­gres­sion-free sur­vival was 8.8 months (related journal article ^[9]).

As already mentioned, in the bb2121 trial, patients had a median of 7-8 prior ther­a­pies, the re­sponse rate was 81 per­cent in patients who re­ceived an active dose of the drug, and pro­gres­sion-free sur­vival was 11.8 months in active-dose patients.

Additional In­for­ma­tion

For more in­­for­ma­tion about the bb2121 re­­sults pre­sented at ASCO last week, please see the re­lated abstract ^[10] and presentations slides ^[11] (PDF, courtesy of Dr. Raje).

A Phase 2 clin­i­cal trial of bb2121 known as “KarMMa” is cur­rently underway at centers in the United States, Canada, and Europe. It will recruit close to 100 re­lapsed myeloma patient. More in­­for­ma­tion is avail­able at this page at clin­i­caltrials.gov ^[12].

Finally, it is worth noting that another CAR T-cell ther­apy being devel­oped as a poten­tial myeloma treat­ment also targets BCMA, the pro­tein targeted by bb2121. The other drug, known as JNJ-68284528, is being devel­oped by Janssen Pharma­ceu­ticals, a sub­sid­i­ary of Johnson & Johnson.

A Phase 1b/2 clin­i­cal trial ^[13] of JNJ-68284528 is ex­pec­ted to start later this year. The Janssen drug is based on the CAR T-cell ther­apy LCAR-B38M originally devel­oped by the Chinese com­pany Legend Biotech (see related press re­lease ^[14]). Results of a Phase 1 trial of LCAR-B38M carried out in China were re­ported at last year’s ASCO meeting (related ASCO 2017 abstract ^[15]). The re­­sults, which showed that 100 per­cent of trial partici­pants responded to treat­ment with LCAR-B38M, attracted sig­nif­i­cant attention.