Bispecifics Could Be A Threat To CAR-Ts
But Efficacy May Trump Convenience
Executive Summary
T-cell-engaging bispecific antibodies emerged at ASH as viable competitors for autologous T-cell therapies, but while their off-the-shelf availability is intriguing, it may be too early to say if their safety and efficacy beats CAR-Ts.
Bispecific antibodies that are designed to target cancer cells and engage T-cells gained momentum at the recent American Society of Hematology (ASH) conference, prompting the question of whether these candidates could steal market share from chimeric antigen receptor T-cell (CAR-T) cell therapies that have generated a lot of excitement over the past few years.
It is probably too early to tell if bispecifics will offer efficacy and safety that beats the response rates seen with CAR-T therapies to date, including the two approved CD19-targeting CAR-T products – Novartis AG’s Kymriah (tisagenlecleucel) and Yescarta (axicabtagene ciloleucel) from Gilead Sciences Inc.’s subsidiary Kite Pharma Inc. However, bispecifics may have safety advantages, with lower rates of severe cytokine release syndrome (CRS) and limited neurotoxicity.
“I think one of the more exciting themes of the meeting is how bispecific antibodies are encroaching on the domain of CAR-T cells,” ASH secretary Robert Brodsky, of the Johns Hopkins University School of Medicine, said during a preview of the December 2019 conference. “More follow-up needs to be done to see the durability and to see the tolerability, but if bispecific antibodies can do what CAR-T cells do, that would be a big advance.”
With similar or better safety and efficacy, there is a lot of potential for the CAR-T therapies to lose ground to T-cell-engaging bispecifics, because the dual-targeting antibodies are off-the-shelf products. The first generation of CAR-T products are autologous therapies, requiring removal of a patient’s cells, which are reengineered to target a specific antigen, then infused back into the patient – a process that can take weeks.
The one-time therapies also launched with list prices starting at $373,000, which is likely two or three times the annual cost of an antibody therapy. In addition, CAR-Ts come with potentially hefty upfront hospital costs, since most recipients are treated in the intensive care unit and monitored for several days to see if patients develop severe CRS or neurotoxicity.
Xencor Inc. CEO Bassil Dahiyat, whose company specializes in bispecifics and targeted antibodies, said that it was not clear if there was market share to steal from CAR-T therapies, given that their use has been limited to date by patient access issues.
“I think there's a mind share that has to be readjusted among investors and the medical community, all of whom are heavily vested in CAR-T based on their amazing promise, but [they] are recognizing the challenges for how they're going to be deployed as therapies,” Dahiyat said.
CAR-T Therapies Have A Timing Advantage
Nevertheless, Kymriah, Yescarta and even Bristol-Myers Squibb Co.’s CD19-targeting lisocabtagene maraleucel (JCAR017 or liso-cel), which was filed for US Food and Drug Administration approval on December 18, have several months and even multiple years of data more than the developers of bispecifics in multiply relapsed or refractory (r/r) non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL) – and for Kymriah in pediatric acute lymphoblastic leukemia (ALL) as well. (Also see "The Case For CAR-T Grows As Responses Hold Up Longer Term" - Scrip, 20 Dec, 2018.)
Among the most prolific class of bispecific T-cell engagers are candidates targeting CD20 on lymphoma cells and CD3 on T-cells, and some of the most advanced candidates are mosunetuzumab from Roche’s Genentech Inc. and REGN1979 from Regeneron Pharmaceuticals Inc. Both companies presented data at ASH along with Genmab AS for GEN3013 and Xencor for XmAb13676.
Roche/Genentech’s anti-CD20 monoclonal antibody Rituxan (rituximab) plus chemotherapy (R-CHOP) is the standard-of-care in earlier lines of B-cell malignancy treatment, so the initial bispecific antibodies are following a long-established precedence for using CD20-directed therapies in NHL.
But as with CAR-T therapies, CRS is a common side effect for the bispecifics. However, higher response rates due to the CD3-targeting component of the CD20 bispecifics may sway prescribers – at least in the later lines of treatment for relapsed and refractory NHL, if not in earlier lines of therapy.
“The hypothesis is that this higher efficacy will translate into better than standard-of-care efficacy in early-line treatment and that CRS can be minimized to the point that the drug can be used in the community setting,” Bernstein analyst Ronny Gal said in a pre-ASH note about the bispecific landscape.
With CAR-T therapies, patients must be treated with the one-time infusions in treatment centers certified to use the T-cell therapies and monitor patients for side effects. These hospital stays can add significantly to already high CAR-T costs – Kymriah launched with a $475,000 price tag to treat pediatric and young adult ALL, while Yescarta hit the market for NHL at a list price of $373,000.
Gal estimated that the later-line CD20xCD3 bispecifics market could total $1.7bn, but earlier lines of treatment could add up to a $7.6bn market, if response rates hold up over the long term and the drugs provide lasting remissions for a meaningful number of patients.
It is difficult to make cross-trial comparisons, but data for bispecific antibodies targeting CD20 and CD3 showed impressive response rates at ASH in relapsed and refractory NHL and DLBCL patients who were treated with several prior lines of therapy. Safety appears to be similar or slightly better than CAR-T therapies in terms of CRS, but with much lower rates of neurotoxicity, especially severe neurological events. (See table below for highlights of data presented for CD20xCD3 bispecifics from Genentech, Regeneron, Genmab and Xencor.)
Biomedtracker analyst David Dahan noted that the bispecific versus CAR-T debate was discussed during the 8 December plenary session in which data for mosunetuzumab were presented.
“During the intro to the plenary, Dr. Georg Lenz from the University of Muenster noted that while CAR-T therapies represent an effective approach for DLBCL, not all patients respond and some patients who respond eventually relapse,” Dahan said. “The plenary included data showing that mosunetuzumab was effective in NHL patients who received prior CAR T-cell therapy. The ORR was 39% (n=7/18) and 22% (n=4/18) achieved a CR.”
“I don’t think that bispecifics match the CAR-Ts on efficacy, but their off-the-shelf nature and lower price make them a good option for patients who have failed CAR-Ts or as earlier lines of therapy,” he added. “Mosenutuzumab continues to be evaluated in several Phase I/II trials including in combination with Polivy (polatuzumab vedotin; Roche) and as first-line therapy.”
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Mosunetuzumab (Genentech) |
CD20-TCB (Genentech) |
REGN1979 (Regeneron) |
GEN3013 (Genmab) |
XmAb13676 (Xencor) |
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Response Rates |
ORR of 62.7% (n=42/67) and CR rate of 43.3% (n=29/67) in slow-growing NHL; ORR of 37.1% (n=46/124) and CR rate of 19.4% (n=24/124) in aggressive NHL. Also, 82.8% (n=24/29) with slow-growing NHL were in remission for up to 26 months and 70.8% (n=17/24) with aggressive NHL were in remission for up to 16 months. |
In combination with Gazyva (obinutuzumab), ORR of 54% (n=15/28) and CR of 46% (n=13/28) in B-cell NHL, including ORR and CR of 66.7% (n=4/6) in follicular lymphoma; ORR of 50% (n=11/22) and CR of 40.9% (n=9/22) in aggressive NHL. |
Data were reported for 96 patients with B-cell NHL, but among those treated with the three highest of six doses, five of eight patients with DLBCL responded and all had complete responses. |
In B-cell NHL at 0.76mg or higher dosed weekly in the first two cycles and less frequently in later cycles, ORR was 36.8% (n=7/19) with one CR (5.3%) and six partial responses (31.6%). |
Among 18 patients with DLBCL treated with 80mcg/kg to 170mcg/kg doses, ORR was 39% (n=7) and CR was 28% (n=5). |
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Safety |
CRS rate was 28.9%, including 20% with grade 1 and 1.1% with grade 3; 3.7% had grade 3 neurological events. |
CRS observed in 67.9% (n=19/28), most of which was grade 1 or 2. |
55 out of 96 patients had CRS, including seven with grade 3 CRS. There was no grade 4 or 5 neurotoxicity, but two grade 3 treatment-related events. |
No neurotoxicity, but CRS rates for all doses were 48.4% (n=15/31) with no grade 3 or higher CRS. |
Among 53 NHL and CLL patients, the CRS rate was 53%. Before step-up dosing was implemented, there were three cases of grade 3 or 4 CRS (6%). The rate of neurotoxicity was 45%, but most cases were mild to moderate. |
More Trials Planned As Bispecifics Advance
Xencor has one of the earliest CD20xCD3 bispecifics in the clinic and CEO Dahiyat said that the company has data now that will help it understand how to differentiate its molecule going forward.
“We’ve reached dose levels where we’re starting to get a picture that positions us to likely be able to dose escalate and hopefully to be able to drive further efficacy, and we think that will position us well to take the next step in development,” Dahiyat noted.
Genmab CEO Jan van de Winkel said that the company will reveal its strategy next year for broadening the development of GEN3013, which comes from the antibody specialist’s DuoBody platform for the discovery of bispecifics. “For the DuoBody CD3xCD20 program, we are going to scale it up,” van de Winkel said. “We hope to move up the number of clinical trials [and] we will actually broaden it in B-cell cancers – we’ll go broader than just non-Hodgkin lymphoma.”
Nancy Valente, senior vice president for oncology product development at Genentech, noted the multiple ways in which the company is testing the mosunetuzumab and CD20-TCB. Both target CD20 on the surface of B-cells and CD3 on T-cells, but they differ in structure.
Valente said that CD20-TCB was tested in combination with Genentech’s anti-CD20 antibody Gazyva, because “CD20-TCB and Gazyva have different proposed mechanisms of action and are thought to target cells in complementary ways. Studying them in combination may allow for the targeting of multiple synergistic pathways in cancer cells and could improve therapeutic outcomes.”
She noted that “we have a broad bispecific development program looking at various lines of therapy and combinations, including immunotherapy and targeted therapies, to better understand how these therapies could provide the best possible outcomes for patients.”
Dahiyat said Xencor also is exploring combination regimens to boost efficacy, because “historically it's been very clear that different mechanisms together in B-cell malignancy and lymphoma do often create more than the individual pieces.”
Even with longer-term data for mosunetuzumab than its competitors, Valente said clinical trial results for both of Genentech’s bispecific antibodies are early and more data are needed to understand how they will best benefit patients. While bispecific antibodies eventually may change the way NHL is treated, she said that whether or not bispecifics will best CAR-T therapies can only be determined with head-to-head trials.
Longer-Term CAR-T Data Also Show Durability
Updated results at ASH from the pivotal ZUMA-1 study of Kite’s commercial CAR-T therapy Yescarta in third-line or later large B-cell lymphoma – including NHL – showed that 47% of patients (n=47/101) were alive after three years of follow-up with median overall survival of 25.8 months. Yescarta was approved based on a 72% ORR and a 51% CR rate with grade 3 or greater CRS observed in 13% of patients and grade 3 or higher neurotoxicity in 31%.
Kite also reported results at ASH from the ZUMA-2 study for a second CD19-targeting candidate, known as KTE-X19, in mantle cell lymphoma (MCL), which was submitted for US FDA approval on 11 December for the treatment of relapsed or refractory MCL.
Results at ASH in 256 evaluable large B-cell lymphoma patients treated with Bristol’s liso-cel – acquired in the recently closed $76bn purchase of Celgene Corp. – showed a 73% ORR and 53% CR rate. CRS occurred in 42% of patients (n=113/269) with 30% (n=80/269) experiencing neurotoxicity, but grade 3 or higher events were reported in only 2% (n=6/269) and 10% (n=27/269), respectively.
More BCMA Bispecifics Emerge In Multiple Myeloma
Bristol also has a major stake in CAR-T therapies for multiple myeloma that target B-cell maturation antigen (BCMA), another class where bispecific antibodies are emerging with new data. Bristol, via the Celgene buyout, and partner bluebird bio Inc. are likely to be the first to seek US FDA approval for a BCMA-targeting CAR-T, but Johnson & Johnson’s Janssen Pharmaceutical Cos. and partner Legend Biotech Corp. are close behind with JNJ-4528 – a candidate with standout data at ASH.
Amgen Inc. did not provide updated results for its bispecific T-cell engager (BiTE) AMG 420 at this year’s meeting, but the company reported early results at ASH in 2018.
BMS presented early results for its own bispecific targeting BCMA and CD3, called CC-93269, this year at ASH and Regeneron had data from seven patients treated with its BCMAxCD3 bispecific REGN5458. Bernstein’s Gal said in an 8 December note that expectations of similar efficacy to CAR-T therapies with better safety for bispecific antibodies did not play out in the BCMA class.
He noted that while the ORR was 89% and the CR rate was 44.4% for nine multiple myeloma patients treated with the highest dose of BMS’s CC-93269, 23 out of 30 patients treated across all doses of the bispecific experienced CRS, including one who died, which was “not so different than the CAR-T.”
CRS was observed with the BMS/bluebird BCMA-targeting CAR-T bb2121 in 83.6% of the 128 patients assessed in the pivotal KarMMa study with a 5.5% rate of grade 3 or higher CRS, including one death; neurotoxicity occurred 18% of patients, but the most severe neurological events were grade 3 toxicities observed in four patients (3.1%). In terms of efficacy, the ORR for bb2121 was 73.4% in KarMMa with a 31.3% CR rate after a median of 11.3 months of follow-up.
Janssen/Legend’s JNJ-4528 had an impressive 100% ORR in 29 patients and a 69% CR rate with a median six months of follow-up. Safety results for JNJ-4528 included CRS in 93% of multiple myeloma patients, but 86% were grade 1 or 2 cases; there was one grade 3 CRS event and one death due to CRS. Neurotoxicity occurred in three patients (10%), including one grade 3 neurological event.
Like BMS, Janssen also has multiple modalities targeting BCMA in the clinic, including a bispecific antibody targeting BCMA and CD3.
At ASH, Regeneron reported no neurotoxicity and three cases of grade 1 and 2 CRS cases among the first seven patients treated with its BCMAxCD3 bispecific REGN5458. Four of the seven patients responded to treatment (57%).
“The current datapoints add to our understanding by telling us that bispecifics' safety is not categorically better than CAR-Ts,” Bernstein’s Gal said of the BCMAxCD3 bispecifics. “Once you get high enough with your efficacy dose, you seem to get similar side effect profiles. It may be somewhat lower in intensity/frequency, but that is yet to be seen.”
He also noted that “at the current stage of development, it seems both CAR-T and bispecifics against BCMA will be primarily used as late line therapy. It will be challenging to move into earlier lines given availability of solid agents in the first and second line,” such as BMS’ Celgene-developed multiple myeloma blockbuster Revlimid (lenalidomide).
Data For Additional Bispecifics Coming Soon
Xencor’s Dahiyat expects the bispecific field to continue broadening into new areas with novel drug targets, now that a lot of companies have figured out how to engineer their antibodies to safely and effectively attach to two targets at the same time and to mediate CRS and other potential side effects from activating T-cells.
“Now that we've learned from those lessons and done a lot of those experiments preclinically, the field is poised to expand even further with a whole new range of targets that are enabled by having the ability to be selective and tunable,” he said.
Both Xencor and Genmab have multiple bispecific antibodies in development and see them as major contributors to their portfolios going forward. At Genmab, in particular, van de Winkel noted that more than 75% of its R&D pipeline comes from the company’s DuoBody platform for bispecifics. The CEO said there’s room for multiple modalities in the market.
“It’s important for us to have options available for new patients and also for patients relapsing a few times, which cannot be treated with other technologies,” van de Winkel said. “But I think that bispecific approaches are definitely going to catalyze a little the growth in the treatment landscape in the coming years.”
This article was first published by In Vivo's sister publication Scrip, December 19, 2019.