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ASH 2022: Bispecific Antibodies

Publication
Article
Evidence-Based OncologyJanuary 2023
Volume 29
Issue 1
Pages: SP22-SP25

Coverage from the 64th Annual American Society of Hematology Meeting and Exposition, December 10-13, 2022, New Orleans, Louisiana.

More Than 70% of Heavily Pretreated Patients Taking Talquetamab for Multiple Myeloma See Responses That “Deepen Over Time”

More than 70% of patients with multiple myeloma had responses, and about a quarter had complete responses, to the bispecific antibody talquetamab even after progressing on a half-dozen other treatments—which for some included chimeric antigen receptor (CAR) T-cell therapy.
Ajai Chari, MD, professor of medicine and director of clinical research in the Multiple Myeloma Program, Mount Sinai, New York, New York, presented combined results from phase 1 and 2 from the MonumenTAL-1 study (NCT03399799) on December 10, 2022, at the 64th American Society of Hematology (ASH) Meeting and Exposition in New Orleans, Louisiana. Results from phase 1 were simultaneously published in the New England Journal of Medicine (NEJM).1

The combined data, which involved 288 patients with a median of 5 prior lines of therapy, produced overall response rates of 74.1% for patients treated a dose of 405 µg/kg weekly and 73.1% for patients treated with 800 µg/kg every 2 weeks, with a median duration of response of 9 months or longer. Both doses were given subcutaneously.

Chari emphasized during his presentation that patients responded quickly to talquetamab; the median time to the first response was just over a month, with a median of 2.2 months to the best response for the lower dose tested given weekly. The mean time to best response was 2.7 months for the larger dose, given every 2 weeks.2

This means that three-quarters of these patients are looking at a new lease on life,” said Chari. “We’re hoping that this will soon become available so that patients can benefit.”

What Chari called “incredible” responses were maintained across important subgroups, including high-risk patients; even patients with extramedullary disease saw response rates of 50%. “We don’t even know how long the remissions last. So this is really life changing for these patients,” he said during a news briefing.

Talquetamab is being developed by Janssen, which paid for the study.
As the investigators explained in the NEJM article, the explosion of treatment options in multiple myeloma means patients are living longer, but the downside is that nearly all will relapse. Thus, the hunt for new therapies continues. The authors state that patients who are triple-class-refractory, meaning they are refractory after receiving a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody, have a poor prognosis.

The arrival of CAR T-cell therapies in multiple myeloma—idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel)—is an important advance but it brings with it the need to address patients who fail these treatments. Also, the customized nature of CAR T-cell therapy brings its own challenges, as some clinicians have reported that manufacturing issues create difficulty in delivering these therapies to multiple myeloma patients who could be candidates.3

Talquetamab, an off-the-shelf product, targets both CD3 and a G protein–coupled receptor, family C, group 5, member D (GPRC5D). The latter is an orphan receptor expressed in malignant plasma cells that works by redirecting T cells to mediate killing of GPRC5D-expressing myeloma cells.
“A substantial percentage of patients with relapsed or refractory multiple myeloma who received talquetamab had a response, and the responses continued to deepen over time,” the investigators wrote in the NEJM article.

“As a bispecific antibody, talquetamab can be readily available off the shelf with convenient subcutaneous administration, so that potential delays, attrition, and the burden associated with generating patient-specific CAR T-cell therapy can be avoided,” they wrote. Talquetamab therapy also led to responses in patients who had received previous T-cell–redirecting therapies targeting BCMA. “These findings suggest that an effective immune response can be mounted against a different antigen even after previous exposure and disease progression with T-cell therapy.”

Multiple doses. The phase 1 data outlined in the NEJM article first examined multiple doses of talquetamab, either intravenously weekly or every other week in doses ranging from 0.5 to 180 µg per kilogram of body weight, or subcutaneously weekly, every other week or monthly, in doses from 5 to 1600 µg per kilogram. Patients in phase 1 had received a median of 6 prior lines of therapy or could not receive standard therapies without unacceptable side effects.

For this portion of the study, the primary end points were the frequency and type of dose-limiting toxic effects, adverse events (AEs), and laboratory abnormalities; these were used to pinpoint which doses would be evaluated in the next phase. For phase 2, the doses selected were 405 µg per kilogram weekly and 800 µg given every other week.

For phase 1, the median age of the patients receiving an intravenous dose was 65 years, with 31% over age 70 years; the median age receiving a subcutaneous dose was 64 years, with 28% over age 70 years. For the combined phase 1/2 study, the median age was 67 years.

Black patients made up 14% of the enrollment in the intravenous group and 10% of the enrollment in the subcutaneous group; these rates are nearly on par with Black representation in the overall US population but below the share of Black patients with multiple myeloma, which is about 20%, according to the International Myeloma Foundation.4 For the combined phase 1/2 data, the share of Black patients dropped to 8.4% for the 405-µg dose and 6.2% for the 800 µg dose.

Presentation at ASH. Chari’s presentation revealed combined results from phase 1 and phase 2 for the first time. A total of 143 patients received the 405-µg/kg weekly dose, while 145 patients received the 800-µg/kg biweekly dose. More than 92% of patients at both doses in the combined phase 1/2 population had received an anti-CD38 monoclonal antibody; 74.1% of the lower dose were triple-class refractory, as were 69% of those receiving the larger dose.

In the combined phase 1/2 group, at the 405-µg dose, 23.8% of patients achieved a stringent complete response (sCR), 9.8% saw a CR, 25.9% saw a very good partial response (VGPR), and 14.7% saw a PR. At the 800-µg dose, 20.0% saw a sCR, 12.4% saw a CR, 24.8% had a VGPR, and 15.9% had a PR.
Duration of response was 7.5 months (95% CI, 5.7-9.4) for the 405-µg dose and 11.9 months (8.4-NE) for the 800-µg dose.

Patient safety. Common AEs were cytokine release syndrome (CRS), seen in 32.2% and 31.7% of the patients in the 2 dose levels, which was less than half of the overall CRS rate seen in the overall phase 1 study. Changes to patients’ nails and skin were common toxic effects, both in phase 1 and in the combined phase 1/2 data. In the phase 1/2 data, infections were seen in 57.3% and 50.3% of the lower and higher doses, respectively; grade 3/4 events occurred in 16.8% and 11.7% at the 2 doses.

The toxicity profile is key, especially the lack of cytopenias, Chari said. “This is very important for myeloma. The No. 1 cause of morbidity and mortality in these patients is infection, and some of the other agents that are generating a lot of interest have significant infectious complications.”

Five patients in the lower dose group and 4 in the higher dose group died of opportunistic infections; 13 patients total developed COVID-19, and 2 patients died from COVID-19. But Chari emphasized that patients showed some ability to develop antibodies following vaccination, which is important for patient safety.

Chari noted that a phase 3 study is ongoing (NCT05455320) evaluating talquetamab against approved therapies, and multiple phase 1 studies are studying its use in combination with other agents.

References
1. Chari A, Minnema MC, Berdeja JG, et al. Talquetamab, a T-cell–redirecting GPRC5D bispecific antibody for multiple myeloma. N Engl J Med. 2022;387(24):2232-2244. doi:10.1056/NEJMoa2204591
2. Chari A, Touzeau C, Schinke C, et al. Talquetamab, a G protein-coupled receptor family C Group 5 member D x CD3 bispecific antibody in patients with relapsed/refractory multiple myeloma (RRMM): phase 1/2 results from the MonumenTAL study. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract 157. https://ash.confex.com/ash/2022/webprogram/Paper159707.html
3. Goodman A. Patients with multiple myeloma may face CAR T shortages. The ASCO Post. September 25, 2022. Accessed December 10, 2022. https://bit.ly/3jbgRCl
4. Disparities in African Americans. International Myeloma Foundation. Accessed December 10, 2022. https://bit.ly/3G14cuM

Blinatumomab Significantly Improves OS in Patients With Newly Diagnosed B-ALL Who Are MRD Negative After Initial Treatment

Consolidation therapy with blinatumomab significantly improves overall survival (OS) in adult patients with a new diagnosis of B-cell acute lymphoblastic leukemia (B-ALL) who had no measurable residual disease (MRD negative) following initial treatment, according to results presented December 13, 2022, at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition, held in New Orleans, Louisiana.

Findings from the phase 3 ECOG-ACRIN E1910 trial (NCT02003222) presented in a late-breaking session by Mark Litzow, MD, professor of medicine, Division of Hematology at Mayo Clinic in Rochester, Minnesota, show that blinatumomab (Blincyto; Amgen) has broader use in early treatment beyond its current approval.1 Today indications are for treatment of adult and pediatric patients with B-ALL who are MRD positive and in remission, or for patients who do not respond to chemotherapy or relapse after first-line treatment. Blinatumomab is also indicated for patients with Philadelphia chromosome-positive relapsed or refractory B-cell precursor ALL.2

Data for this interim analysis show that patients receiving blinatumomab with consolidation chemotherapy had an OS of 83% compared with 65% among those receiving consolidation chemotherapy alone. In a news briefing, Litzow showed that the survival curve for the blinatumomab arm has plateaued while the curve for the control arm continues to fall.

Blinatumomab is among the bispecific antibodies that were the stars at the 2022 ASH meeting, stealing the limelight that chimeric antigen receptor T-cell therapies have held in recent years. As Litzow explained, blinatumomab is a bispecific T-cell engager molecule, which works by bring a normal T cell in proximity with a leukemia blast cell, killing it.

Why give blinatumomab to patients who are MRD negative? “We know that even though we can’t find leukemia in these patients’ bone marrow, it’s still hiding there,” Litzow said during a news briefing.

The trial enrolled 488 adults at 77 sites in the United States, Canada, and Israel. Patients received a course of standard combination induction chemotherapy for 2.5 months. Those who were in remission after this treatment moved on to an intensification phase, which aimed to keep the leukemia from reaching the central nervous system, where relapse often occurs. MRD status was tested at a central laboratory and patients were randomly assigned to receive either a standard course of consolidation chemotherapy or chemotherapy with 4 cycles of blinatumomab.

Both arms received maintenance therapy and were monitored for 2.5 years, and Litzow explained that treating physicians had the option to refer patients for stem cell transplant.

Results. In a planned interim analysis at 43 months, the median OS for the chemotherapy-alone arm was 71.4 months while the median OS for the blinatumomab with chemotherapy arm was not reached (HR, 0.42; 95% CI, 0.24-0.75; P = .003).

Across both arms, at the time of the interim analysis 17 patients in the blinatumomab arm and 39 receiving chemotherapy alone had died.
During the briefing, both Litzow and ASH Secretary Cynthia Dunbar, MD, chief of the Translational Stem Cell Biology Branch within the Intramural Research Program of the National Heart, Lung, and Blood Institute at the National Institutes of Health, said the findings were practice changing.

“Patients who are MRD negative have a better prognosis than patients who are MRD positive, generally, but they still relapse,” Litzow said in a statement. “We think we can do better, so we wanted to see if blinatumomab would improve the results in this already somewhat favorable risk group, and the study showed that it did.”3

The randomized trial was conducted by the National Cancer Institute Clinical Trials Network.

References
1. Litzow MR, Sun Z, Paietta E, et al. Consolidation therapy with blinatumomab improves overall survival in newly diagnosed adult patients with B-lineage acute lymphoblastic leukemia in measurable residual disease negative remission: results from the ECOG-ACRIN E1910 randomized phase 3 National Cooperative Clinical Trials Network Trial. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract LBA-1. https://ash.confex.com/ash/2022/webprogram/Paper171751.html
2. FDA grants regular approval to blinatumomab and expands indication to include Philadelphia chromosome positive B-cell. FDA. July 17, 2017. Accessed December 13, 2022. https://bit.ly/3HW2qMX
3. Blinatumomab further improves survival among B-lineage ALL patients with a good prognosis. News release. American Society of Hematology. December 13, 2022. Accessed December 13, 2022. https://bit.ly/3FvXR9c

SPOTLIGHT: Ajai Chari, MD, Discusses Mechanism of Talquetamab, Importance of Bispecifics

Phase 1/2 data from MonumenTAL-1 (NCT03399799), presented at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition show talquetamab induced a substantial response among patients with heavily pretreated relapsed or refractory multiple myeloma, including some patients with prior chimeric antigen receptor (CAR) T-cell therapy. In an interview with Evidence-Based Oncology™ (EBO), Ajai Chari, MD, professor of medicine, director of clinical research, Icahn School of Medicine at Mount Sinai, explained why the bispecific antibody is a good choice for patients who have received multiple prior therapies.
This interview has been lightly edited for length and clarity.

EBO: Why does the mechanism of action for talquetamab make it a good choice for patients who have received multiple prior therapies, including CAR T-cell therapy?

Chari: The first monoclonal antibody for any human being involved a myeloma cell, and the scientists were given the Nobel Prize in the 1980s.1 I always like to start everything about antibodies in general with that statement because they fused a spleen cell to a myeloma cell and every antibody in human beings today owes its legacy to myeloma. But it wasn’t until 30 years later that we got naked antibodies, and then now, for the first time, we have bispecific antibodies. The difference between a naked antibody and a bispecific antibody is the bispecific has 2 binding sites, if you will. Here, 1 site binds to the myeloma and the other site binds to the T cells.

You can think of cancers like myeloma as occurring due to a lazy immune system, because if the T cells are able to generally monitor cancers and detect them early, they should be eradicating them; if they don’t, they’re failing. We know 1 way of getting around that is to take them out and genetically modify them in CAR T. Here, the difference is this is an off-the-shelf product. You don’t need this complicated collection, manufacturing, bridging—this is ready to go....The binding of both components—the tumor and the T cell—basically traffics the T cells to where the cancer is; the T cells release chemicals like perforin, granzymes [that] poke holes in the cancer membrane, and you have cell death. So, it’s bringing your army to the enemy.

EBO: Based on the phase 1 results, will 1 dose or method of delivery be the preferred option?

Chari: In the phase 1 study, which just came out in the New England Journal of Medicine (NEJM),2 a variety of doses were studied both intravenously (IV) and subcutaneously. The decision was made to go more with subcutaneous, least of all because of physicians. Because what do we do? We just sign the orders. But for everybody else in the health care team, it makes a big difference. For the pharmacists, it’s much easier to mix the drug. For the nurses who are administering the drug, it’s a shot instead of a long drip.

And finally, for the patient, you’re decreasing the time they’re spending in clinic….It does change the properties of the drug because when you give a drug IV it gets absorbed very quickly. With subcutaneous administration, it has a delayed absorption, so when you think about things like cytokine release syndrome, which is 1 of the main side effects, this happens earlier with an IV drug compared with the subcutaneous drug of the same formulation. That was really important for the phase 1 study. The New England Journal is showing that the drug works and the safety profile was characterized. But here at this year’s ASH meeting, what’s new is, for the first time, we’re presenting the phase 2 part of the study where we’re clarifying the efficacy and the safety as well.3

EBO: The NEJM paper discusses the value of the off-the-shelf nature of talquetamab. Do you expect this treatment to be used after CAR T-cell therapy or possibly before, since administration might be less challenging?

Chari: I’ll answer this with the debate that I had to do for the European Hematology Association this year. I was assigned bispecific—maybe I have a slight bias. I do believe in CAR T. I’ve sent many, many patients to CAR T—it’s a fantastic treatment. The best way to answer that question is imagine a hypothetical randomized study. Every patient signs the consent and the computer decides whether they go to CAR T or bispecific. If you did that, unless the progression-free survival of the CAR T is over a year, I would put my money on a bispecific. Why is that? Because all the CAR T data that have been coming from clinical trials to date have been extremely selected. I can tell you at our institution, for example, when we had the CAR T studies open at Mount Sinai, at any given time, we might have 50 patients that we wanted to take CAR T. And so when we got that magical elusive spot, 1 a month, you had to have the patient that was progressing. You now whittle that down. And of those, you’re going to pick the youngest, fittest patient with the least medical problems who’s got the most stable disease, and they get the spot and then [their cells] get collected, then they have their manufacturing period, and then they actually get dosed. And there’s this term in medicine called intention to treat—if you accounted for every single patient that signed the consent, and not who actually got to the CAR T infusion, you can imagine with rapidly progressing patients, a lot of them aren’t going to be able to get to CAR T. And that’s why we need these off-the-shelf products—because patients can’t wait. And if your disease is progressing, and you have to wait 6 weeks or a month to get a CAR T slot [for] collection, and then another 8 weeks after that, what’s going to control the myeloma in a patient—especially 1 that exhausted all the therapy? I think the reason for these off-the-shelf products is first and foremost for those explosive disease patients. And secondly, perhaps for elderly patients or frail patients who may not tolerate the cytokine release syndrome that can be a little bit more aggressive with CAR T. Those are some reasons. And then the third reason goes back to the other part of the question…The answer is yes, both because we haven’t cured everybody with myeloma. That means that if you relapsed after CAR T you need a bispecific. And if you get bispecific and you relapse, you still need the CAR T, so until we get cures, everybody gets everything. It’s just a matter of sequencing. And for that, we need more studies and information to do the right sequencing.

EBO: Enrollment of Black patients in the phase 1 part of the study was on par with representation in the overall US population, but still short of the percentage in the US population who have multiple myeloma. How do you feel the study team did in meeting goals of diversity in clinical trial enrollment?

Chari: Diversity is a huge issue. We know that there’s more myeloma among African Americans and yet they’re not as well represented in clinical trials. It’s a multiprong problem. I think part of it is getting the referral to the academic institutions where these studies are being done. Access is a big part of it. For example, in the Veterans [Administration] hospitals, where patients get the same treatment and have same insurance—everything’s the same—the outcomes for Black patients and non-Black patients are identical….For a variety of reasons, patients aren’t even being offered participation.

I can tell you at Mount Sinai, at our site, our patient population and clinic is about 20% African American. And that’s exactly what we have in our clinical trials. But we’re just 1 site amongst many, although I’m proud to say that our site accrued about 100 patients on this study between part 1 and part 2. So we do have a sizable contribution of African Americans patients on this study. And in fact, 1 of my patients who has agreed to do some testimonials is herself an African American and she’s a nurse. So who better to talk about the importance of participating in clinical trials than a health care professional who comes from a community that’s underrepresented?
But I think collectively we need a better effort, and that’s not just going to be any one group. It’s going to have to be academia, nonprofits, patient organizations, and advocacy groups. [For] the regulatory bodies, one way to do that is to mandate that some studies will have a certain representation and a cohort specifically designated for African Americans. We also must keep in mind though that these are global studies. And so you’re not going to have as many African Americans in any country, or even Black patients for that matter, depending on where the patients are coming from. It’s a complex issue that we need to think about globally. 

References
1. Nobel Prize in Physiology or Medicine 1984. The Nobel Prize. News release. December 1984. Accessed December 18, 2022. https://www.nobelprize.org/prizes/medicine/1984/summary/
2. Chari A, Minnema MC, Berdeja JG, et al. Talquetamab, a T-cell–redirecting GPRC5D bispecific antibody for multiple myeloma. N Engl J Med. 2022;387(24):2232-2244. doi:10.1056/NEJMoa2204591
3. Chari A, Touzeau C, Schinke C, et al.Talquetamab, a G protein-coupled receptor family C Group 5 member D x CD3 bispecific antibody in patients with relapsed/refractory multiple myeloma (RRMM): phase 1/2 results from the MonumenTAL study. Presented at: 64th American Society of Hematology Annual Meeting and Exposition. December 10-13, 2022; New Orleans, LA. Abstract 157. https://ash.confex.com/ash/2022/webprogram/Paper159707.html

From Lymphomas to Myeloma, Bispecific Antibodies Make a Big Splash at ASH

For several years, chimeric antigen receptor (CAR) T-cell therapies took center stage during the annual meeting of the American Society of Hematology (ASH). Despite their cost, CAR T-cell therapies are no longer treatments of last resort; at ASH 2021 in Atlanta, Georgia, news on the first day focused on bringing rival therapies for diffuse large B-cell lymphoma (DLBCL), axicabtagene ciloleucel (axi-cel, Yescarta), and lisocabtagene maraleucel (liso-cel, Breyanzi), into second-line treatment. During 2022, both were approved for this use.1,2

There’s still plenty of excitement about CAR T, but as seen at ASH 2022 in New Orleans, Louisiana, these customized treatments now share the limelight with bispecific antibodies, which made news across disease states from large B-cell lymphoma (LBCL) to follicular lymphoma (FL) to multiple myeloma (MM). As their name suggests, these treatments aim at 2 targets, increasing their potency against cancer. And for those wondering, yes, there are trispecific antibodies in the works.3

As speakers noted during ASH, bispecifics have pluses and minuses compared with CAR T-cell therapy, which many say is becoming the treatment of choice, especially in second-line DLBCL. But bispecific antibodies are crucial in 2 ways: First, some patients who receive CAR T-cell treatment later progress and need other options. Second, as off-the-shelf products, bispecific antibodies don’t require the multistep process of collecting T cells and waiting for an engineering process that can take up to 6 weeks. For frail patients or those with rapidly progressing disease, a bispecific antibody may be a good option, as Nancy L. Bartlett, MD, wrote in an editorial in the New England Journal of Medicine (NEJM) to accompany papers released during ASH.4

“Many of the logistic limitations of CAR T cells may be addressed by an emerging class of off-the-shelf T-cell–engaging bispecific antibodies,” she wrote. As Bartlett explained, the cancer-killing qualities of these agents results from simultaneous binding of a tumor-associated antigen and endogenous T cells, which triggers T-cell activation.

Although toxicity with these agents varies, Bartlett noted that bispecifics are needed and useful for the 60% of patients who ultimately relapse after CAR T-cell therapy. Experts say they still have much to learn about sequencing the different therapeutic classes, especially as they navigate availability issues in CAR T, which seem particularly acute in MM.5

During ASH, new data involving bispecific antibodies included presentations on glofitamab in LBCL, mosunetuzumab in FL and epcoritamab in B-cell lymphomas. New data was also presented for teclistamab (Tecvayli), which in October 2022 became the first FDA-approved bispecific B-call maturation antigen (BCMA)-directed CD3 T-cell engager for use in relapsed or refractory (R/R) MM.6

Updated Phase 2 Data for Glofitamab in LBCL
Glofitamab is a CD20 x CD3 T-cell-engager with a unique 2:1 configuration, with bivalency for CD20—meaning it redirects T cells to eliminate normal and malignant B cells. The treatment is administered intravenously (IV) for 12 cycles. Data presented at the 2022 American Society of Clinical Oncology in June from an ongoing pivotal phase 1/2 study (NCT03075696) showed a median complete response (CR) of 39.4% (61 of 155 patients) and an overall response rate (ORR) of 51.5% (80 of 155 patients).7 In data presented in New Orleans, patients were pretreated with obinutuzumab to mitigate cytokine release syndrome (CRS) and the option of retreatment was available if patients experienced disease progression. The median number of prior treatments was 3, including 19.6 with prior CAR T-cell therapy (30 of 155 patients); of these, 7 patients achieved CR.8

At ASH 2022, Martin Hutchings, MD, PhD, staff specialist, Department of Hematology, Copenhagen University Hospital presented data in an oral session that focused on duration of CRs in patients with R/R LBCL after the end of treatment. Hutchings offered updated data from the abstract, showing that 12 months after the end of treatment, 61% of patients (n = 37/61) maintained a CR, 92.6% remained progression-free, and 1 patient (n = 1/44) experienced disease progression. The estimated rate of patients with a CR lasting 24 months is 79%, and the median PFS (in months) for those achieving CR is not evaluable (NE; [95% CI, 27.5-NE]).

During the session, Hutchings was asked if glofitamab was a cure. While more follow-up was needed, he said, “I do believe there is a curative potential.” A subcutaneous version of glofitamab is being developed, he said.

A paper based on earlier data from the phase 2 study in R/R DLBCL was published online in NEJM during the conference.9 According to a statement from the drug’s sponsor, Genentech, data the pivotal phase 2 study have been submitted for review to the European Medicines Agency, and at press time FDA had accepted glofitamab for priority review.10

Mosunetuzumab in Follicular Lymphoma
In July 2022, Genentech reported that FDA had granted priority review to mosunetuzumab for patients with R/R FL, saying the therapy could be the first CD20 x CD3 T-cell engaging bispecific antibody approved “for the treatment of any type” of non-Hodgkin lymphoma.11 On December 22, 2022, the FDA approved mosunetuzumab for patients with FL who have received at least 2 prior treatments; the therapy will be marketed as Lunsumio.12

Longer-term data presented at ASH 2022 showed that after a median of 28.3 months of follow-up, mosunetuzumab continued to produce durable responses in patients with FL. In this part of the pivotal phase 2 study (NCT02500407) 60% of patients with 2 more prior therapies experienced a CR of 60% (54 of 90 patients; 95% CI, 49.1-70.2) and 77.8% achieved an objective response, which includes CR plus partial responses (95% CI, 67.8-85.9).13

Among those who achieved CR, after 24 months 62.7% of patients were still in remission (95% CI, 37.7–87.7). Overall, 48.3% remained progression-free (95% CI: 36.2-60.3), and the median duration of response and duration of CR, as well as median PFS were not reached. No new CRS events or adverse events of grade 3 or higher were reported.

Epcoritamab in B-Cell Lymphomas
Other presentations at ASH 2022 offered new data on epcoritamab, an investigational therapy known as a DuoBody-CD3xCD20 bispecific antibody. As described in 2018, this platform “induced potent activation, proliferation and cytotoxic activity of both CD4+ and CD8+ T cells in the presence of CD20-expressing cells.”14 Epcoritamab, developed by AbbVie and Genmab, is being studied in multiple B-cell malignancies, including DLBCL and FL. FDA accepted the therapy for priority review for patients with R/R LBCL after at least 2 prior treatments, with a target action date of May 21, 2023.15

Results presented included updated phase 1/2 data from EPCORE NHL-2 for non-Hodgkin lymphoma, which combines subcutaneous epcoritamab with rituximab, dexamethasone and chemotherapy. Pau Abrisqueta, MD, PhD, of Hospital Universitario Vall d’Hebron in Barcelona, Spain, outlined data for patients with R/R DLBCL who were eligible for autologous stem cell transplant (ASCT). He explained that these patients were all high-risk and highly refractory; under current standard of care, not all patients will make it to ASCT and about half will not have long-term remission. For the 27 evaluable patients in this arm, results showed an 85% ORR (23 of 27 patients) and a 67% (18 of 27 patients) with a complete metabolic response rate. Median time to response was 1.4 months. After a median follow-up of 12.6 months, 16 patients proceeded to ASCT and of this group, “there is no sign of progression,” Abrisqueta said. Median PFS and median OS were not reached; an estimated 90% of patients were alive at 12 months.16

Common treatment emergent adverse events (TEAEs) in this study arm that affected at least a quarter of patients were thrombocytopenia (69%), anemia (51%), neutropenia (44%), CRS (41%), and nausea (31%), and fatigue (28%).
In other results, high response rates for epcoritamab were seen in chronic lymphocytic leukemia with Richter Syndrome17 and in follicular lymphoma, both in R/R patients and those previously untreated.18,19

Teclistamab With Daratumumab, Lenalidomide in MM
More than 90% of patient with R/R MM showed strong responses when treated with a combination of the bispecific antibody teclistamab (Tecvayli) and daratumumab (Darzalex), a monoclonal antibody studied in combination with classic triplet therapy. Teclistamab is a subcutaneous treatment.20

Results from MajesTEC-1 presented at ASH 2021 led to the fall approval of teclistamab.6,21 Data from 32 patients the phase 1b MajesTEC-2 study (NCT04722146), presented December 10, 2022, represent the first results from a triplet regimen using the bispecific antibody. In an interview with Evidence-Based Oncology™ (EBO), Emma Searle, MD, PhD, of The Christie Hospital and the University of Manchester, explained, “The patient population in MajesTEC-2 was less heavily pretreated than the patient population in MajesTEC-1, and we’re seeing very high overall response rates in this combination of near to 94% across the 2 different dosing schedules. Those responses appear to deepen over time.”

At a median follow-up of 8.4 months (1.1 to 12.9 months range), the ORR was 93.5%. Among all patients in the trial, very good partial responses or better were seen by 90.3% of the patients, and 54.8% achieved a CR or better. Median time to response was 1 month. At the time of data cut off, 80.6% of patients were on treatment and did not have disease progression. Median duration of response had not been reached.20

Results from MajesTEC-1 presented at ASH 2021 led to the fall approval of teclistamab.6,21 Data from 32 patients the phase 1b MajesTEC-2 study (NCT04722146), presented December 10, 2022, represent the first results from a triplet regimen using the bispecific antibody. In an interview with Evidence-Based Oncology™ (EBO), Emma Searle, MD, PhD, of The Christie Hospital and the University of Manchester, explained, “The patient population in MajesTEC-2 was less heavily pretreated than the patient population in MajesTEC-1, and we’re seeing very high overall response rates in this combination of near to 94% across the 2 different dosing schedules. Those responses appear to deepen over time.”

At a median follow-up of 8.4 months (1.1 to 12.9 months range), the ORR was 93.5%. Among all patients in the trial, very good partial responses or better were seen by 90.3% of the patients, and 54.8% achieved a CR or better. Median time to response was 1 month. At the time of data cut off, 80.6% of patients were on treatment and did not have disease progression. Median duration of response had not been reached.20

Common AEs were neutropenia (84.4% of any grade, 78.1% grade 3/4) and thrombocytopenia (25% any grade, 15.6% grade 3/4), and CRS (81.3% all grade 1/2); 97% of CRS occurred in cycle 1.

According to Janssen, the MajesTEC-7 study (NCT05552222) will evaluate this triplet regimen in patients with newly diagnosed MM.22

References

1. FDA approves axicabtagene ciloleucel for second-line treatment of large B-cell lymphoma. FDA. Updated April 1, 2022. Accessed December 17, 2022. https://bit.ly/3RqnXzB
2. U.S. FDA approves Bristol Myers Squibb’s CAR T cell therapy Breyanzi for relapsed or refractory large B-cell lymphoma after one prior therapy. News release. Bristol Myers Squibb. June 24, 2022. Accessed December 17, 2022. https://bit.ly/3W45UAY
3. Kuchnio A, Yang D, Vloemans N, et al. Characterization of JNJ-80948543, a novel CD79bxCD20xCD3 trispecific T-cell redirecting antibody for the treatment of B-cell non-Hodgkin lymphoma. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract 1342. https://ash.confex.com/ash/2022/webprogram/Paper168739.html
4. Bartlett NL. Bispecific antibodies in lymphoma—another win for T cells. N Engl J Med. 2022; 387:2285-2286. doi: 10.1056/NEJMe2212732
5. Astor L. Bispecifics vs CAR T-cell therapy: Which is better in relapsed/refractory multiple myeloma? Targeted Oncology. Published October 1, 2022. Accessed December 18, 2022. https://bit.ly/3HO58DO
6. FDA approves teclistamab-cqyv in relapsed or refractory multiple myeloma. News release. FDA website. October 25, 2022. Accessed December 18, 2022. https://bit.ly/3jhKC4r
7. Dickinson M, Carlo-Stella C, Morschhauser F, et al. Glofitamab in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and ≥ 2 prior therapies: Pivotal phase 2 expansion results. J Clin Oncol 2022; 40(suppl 16):7500-7500. doi: 10.1200/JCO.2022.40.16_suppl.7500
8. Hutchings M, Carol-Stella C, Morschhauser F, et al. Relapse is uncommon in patients with large B-cell lymphoma who are in complete remission at the end of fixed-course glofitamab treatment. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract 441. https://ash.confex.com/ash/2022/webprogram/Paper157554.html
9. Dickinson MJ, Carlo-Stella C, Morschhauser F, et al. Glofitamab for relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2022;387:2220-2231. doi:10.1056/NEJMoa2206913.
10. Genetech presents new data demonstrating the potential of glofitamab and mosunetuzumab as fixed duration, off-the-shelf treatment options for lymphoma. News release. BusinessWire. December 12, 2022. Accessed December 18, 2022. https://bwnews.pr/3VetVEa
11. FDA grants priority review to Genetech’s mosunetuzumab for people with relapsed or refractory multiple myeloma. News release. July 5, 2022. Accessed December 18, 2022. https://bit.ly/3BR2l9d
12. FDA approves Genentech’s Lunsumio, a first-in-class bispecific antibody, to treat people with relapsed or refractory follicular lymphoma. News release. Genentech. December 22, 2022. Accessed December 22, 2022. https://bit.ly/3BT9Exa.
13. Budde E, Bartlett NL, Giri P, et al. Subcutaneous mosunetuzumab is active with a manageable safety profile in patients (pts) with relapsed/refractory B-cell non-Hodgkin lymphomas (B-NHLs): updated results from a phase 1/2 study. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract 1628. https://ash.confex.com/ash/2022/webprogram/Paper157729.html
14. Hiemstra IH, Engelberts PJ, Jong B, et al. Duobody-CD3xCD20 shows unique and potent preclinical anti-tumor activity in Vitro and In Vivo, and is being evaluated clinically in patients with B-cell malignancies. Blood. 2018; 132 (suppl 1): 1664. https://doi.org/10.1182/blood-2018-99-115957
15. Genmab announces US Food and Drug Administration accepts for priority review biologics license application (BLA) for epcoritamab (DuoBody-CD3xCD20) for the treatment of relapsed/refractory large B-cell lymphoma (LBCL). News release. Business Wire. November 21, 2022. Accessed December 18, 2022. https://bit.ly/3PHQ1hu
16. Abrisqueta P, Cordoba R, Falchi L, et al. Subcutaneous epcoritamab + R-Dhax/c in patients with relapsed or refractory diffuse large B-cell lymphoma eligible for autologous stem cell transplant: updated phase 1/2 results. Presented at: 64th American Society of Hematology Annual Meeting and Exposition, December 10-13, 2022; New Orleans, LA. Abstract 443. https://ash.confex.com/ash/2022/webprogram/Paper158278.html
17. Kater AP, Ye JC, Sandoval-Sus J, et al. Subcutaneous epcoritamab in patients with Richter’s Syndrome: early results from phase 1b/2 trial (EPCORE CLL-1). Presented at: 64th American Society of Hematology Annual Meeting and Exposition, December 10-13, 2022; New Orleans, LA. Abstract 348. https://ash.confex.com/ash/2022/webprogram/Paper158298.html
18. Falchi L, Abrisqueta P, Nijland M, et al. Subcutaneous epcoritamab with rituximab + lenalidomide in patients with relapsed or refractory follicular lymphoma: phase 1/2 trial update. Presented at: 64th American Society of Hematology Annual Meeting and Exposition, December 10-13, 2022; New Orleans, LA. Abstract 609. https://ash.confex.com/ash/2022/webprogram/Paper158203.html
19. Falchi L, Leslie LA, Belada D, et al. Subcutaneous Epcoritamab in combination with rituximab + lenalidomide (R2) for first-line treatment of follicular lymphoma: initial results from phase 1/2 trial. Presented at: 64th American Society of Hematology Annual Meeting and Exposition, December 10-13, 2022; New Orleans, LA: Abstract 611. https://ash.confex.com/ash/2022/webprogram/Paper158232.html
20. Searle E, Quach H, Wong SW, et al. Teclistamab in combination with subcutaneous daratumumab and lenalidomide in patients with multiple myeloma: results from one cohort of MajesTEC-2, a phase 1b, multicohort study. Presented at: 64th American Society of Hematology Annual Meeting and Exposition, December 10-13, 2022; New Orleans, LA. Abstract 160. https://ash.confex.com/ash/2022/webprogram/Paper159711.html
21. Melillo G. Phase 1/2 trial results underscore teclistamab’s efficacy in RRMM. The American Journal of Managed Care®. Published December 22, 2021. Accessed December 18, 2022. https://bit.ly/3FIfUck
22. Janssen presents first data from MajesTEC-2 trial of TECVAYLI (teclistamab) in combination with Darzalex (daratumumab) subcutaneous (SC) formulation and lenalidomide in relapsed or refractory multiple myeloma. News release. GlobeNewswire. December 10, 2022. Accessed December 18, 2022. https://bit.ly/3YypgzT

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