ASCO 2024 Leukemia & Lymphoma

Improving Treatment Selection and Outcomes for Older Patients With Hematologic Malignancies

With incidence of leukemia in older adults increasing faster than other cancers in this population,¹ the term geriatric hematopoietic stem cell transplantation (HCT) is not such an oxymoron anymore, explained Shannon Rose McCurdy, MD, an oncologist with the University of Pennsylvania Health System.

Shannon Rose McCurdy, MD | Image credit: Doximity

McCurdy chaired a session at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting that delved into the growing need to improve clinicians’ understanding of selecting the best therapies for older patients with hematologic malignancies and the role of geriatric assessments to individual therapy.

Predicting Transplant Outcomes for Older Patients
Compared with chemotherapy consolidation, transplant improves survival for older adults. One study in patients with myelodysplastic syndrome showed the 3-year overall survival was 47.4% for those who received transplantation compared with 16.0% (P < .0001) for those who did not.²

The reason older adults are able to successfully improve survival with transplant is because the transplant conditioning has changed, McCurdy explained. While patients older than 65 years almost never underwent transplant in the early 2000s, there are now about 2000 transplants a year among this population.

“In the early days of transplant, there was very intense kind of conditioning prior to transplant, and this was associated with higher toxicity,” she said. “And over time, we’ve allowed the conditioning intensity to go down, and the bigger reliance now is…to create a graft-vs-tumor effect and cure the malignancy by the stem cells rather than by the intensity of the conditioning.”
The result of reduced intensity for conditioning has been a decrease in nonrelapse mortality.³ There is also better supportive care among patients who undergo transplant, McCurdy said.

As older adults start to represent a greater proportion of transplant recipients, clinicians need better ways to project their outcomes and risk-stratify them prior to transplant, she said. The best resource for nonrelapse mortality risk assessment for transplant has been the hematopoietic cell transplantation–specific comorbidity index (HCT-CI). The patient’s comorbidity score and organ function assessments are used to predict their nonrelapse mortality.

“However, there [have] been some data that in just an older alone population, the HCT-CI score might not be as predictive because older folks are just more inherently going to have comorbidities that are natural with aging and many comorbidities may potentially be compensated for and therefore not affect outcomes,” McCurdy said.

A large trial sought to understand how to best stratify patients beyond just the HCT-CI, including variables such as albumin, C-reactive protein, age, the Karnofsky Performance Scale Index, the Montreal Cognitive Assessment, and weight loss.⁴ In addition, there are geriatric domains and tools that can be used to assess the patient, including functional assessments that can identify frailty, which is the vulnerability to poor resolution of homeostasis after an illness.

Incidence of frailty among patients 60 years and older undergoing HCT may be low (9.8%), according to Fried’s Frailty Phenotype scoring, but 56.2% are considered pre-frail.⁵ In comparison, 44% of patients with newly diagnosed acute myeloid leukemia (AML) are considered frail at diagnosis. Patients considered fit had a much better survival than those who were pre-frail or frail even when limiting the patients to reduced intensity conditioning, McCurdy said. The research also showed that 1 month after the transplant, 65% of older adults had a worsening in frailty and at 3 months 59% still had worse frailty than before HCT.

“Relapse and then death due to relapse is happening more in our frail and pre-frail transplant patients,” she said.

Understanding that frail patients have worse outcomes is not enough, though, unless something can be done to address this. Research has shown that multidisciplinary clinics that can assess and optimize patients prior to allogeneic transplant through interventions such as nutrition, consults, and physical therapy can improve survival in older patients undergoing HCT.⁶

Beyond HCT, geriatric assessments can help identify optimal treatment for older patients with hematologic malignancies. In the community setting, geriatric assessments are a necessary first step to guide decision-making around treatments and improve outcomes for older patients, explained Judith Hopkins, MD, of Novant Health Cancer Institute. In addition to helping select patients for HCT, these assessments can remove the age barrier to care for chimeric antigen receptor T-cell therapy.

As McCurdy explained, these assessments help determine the biologic age and fitness of older patients before undergoing therapy. The comprehensive geriatric assessment is the best way to do that but it can take a long time. The ASCO Practical Geriatric Assessment (PGA) was designed to address community oncologists’ concern about how long the standard assessment takes, which ranges from 10 to 25 minutes.

The ASCO PGA not only addresses time constraint concerns but also identifies the 62% of patients with dependence in 1 or more instrumental activities of daily living (IADLs), the 77% who take 4 or more medications, and the 46% who have 1 or more comorbidities.

“[The geriatric assessment] can help you determine: Is this a patient who is a candidate for an intensive induction chemotherapy regimen?” Hopkins said. “Or is this a patient that might be better with azacitidine and venetoclax? Is the patient going to be a candidate eventually for stem cell transplant?”

Hopkins also discussed which patients should be referred to an academic medical center, such as patients 65 years and older with acute leukemia given that their 5-year overall survival is only 10% to 15%. In comparison, patients with low-risk myelodysplastic syndrome can easily be treated in the community, as can patients with myeloproliferative neoplasms, such as polycythemia vera, myelofibrosis, and essential thrombocythemia. Almost all first-line therapy for multiple myeloma and non-Hodgkin lymphoma
can be done in the community as long as there is a strong blood bank and high-quality imaging with PET and CT scanners.

Potentially, geriatric assessments can also help address over- and undertreatment, but we might not be there just yet, said Gregory Abel, MD, MPH, a hematologic oncologist and outcomes researcher from Dana-Farber Cancer Institute. For example, not offering transplant for an older patient based on age may be considered undertreatment if the patient is independent for ADLs and IADLs, has limited comorbidities, and prioritizes living longer. On the other hand, transplant in a 75-year-old patient who is cognitively impaired and frail in order to minimize the risk of conversion to AML may represent overtreatment.

The Geriatric Assessment for Patients 70 years and older (GAP70+) trial and the Geriatric Assessment–driven Intervention (GAIN) trial both investigated if geriatric assessment could reduce serious toxicity in older patients.^7,8 The studies showed that integrated geriatric assessments alongside standard oncology care reduced severe toxicity from cancer treatment while maintaining efficacy of treatment.

In GAP70+, patients receiving care guided by a geriatric assessment received more treatment modifications that reduced severe toxicity by 15% and functional decline by 20% compared with standard care. GAIN showed an increase in supportive care interventions to minimize negative effects of intense treatments, although geriatric assessment did not influence the intensity of the initial cancer treatment.⁸

“With these studies, a theme that comes up is [that] it’s difficult to disentangle the effects of supportive care from effects of treatment modifications,” Abel said. “Upfront supportive care may improve frailty, boosting physiologic reserve and the ability to tolerate regimens at the doses studied in younger patients. But also, treatment modifications may result in less need for supportive care.”

However, other studies, such as the 5C study, have shown no differences in survival, change in treatment plan, unplanned hospitalizations, or treatment toxicity.⁹ In addition, most trials have had small numbers of patients with blood cancers.

There has been only 1 randomized, controlled trial of patients with blood cancer, which Abel conducted with a team at Dana-Farber. The study assigned pre-frail and frail patients 75 years and older in a 2:1 fashion to receive standard care vs care plus geriatric consultation.¹⁰ Again, geriatric consultation did not have any benefit on 1-year overall survival or unplanned hospitalizations, although patients who received the counseling were more likely to have end-of-life goal-of-care discussions, and they received interventions related to comorbidities, polypharmacy, function, cognition, and falls.

According to Abel, there clearly needs to be more data to assess the impact of cognitive decline, functional limitations, and frailty on outcomes in cancer. More trials are enrolling older adults and frailty is increasingly being measured and considered an end point that is important to older adults.
“At this meeting, we talk a lot about progression-free survival and response rates, but these may be irrelevant to some older adults if the surrogate end points do not covary with functional status or quality-of-life benefits,” Abel said.

References
1. Hao T, Li-Talley M, Buck A, Chen WY. An emerging trend of rapid increase of leukemia but not all cancers in the aging population in the United States. Sci Rep. 2019;9(1):12070. doi:10.1038/s41598-019-48445-1
2. Nakamura R, Saber W, Martins MJ, et al. Biologic assignment trial of reduced-intensity hematopoietic cell transplantation based on donor availability in patients 50-75 years of age with advanced myelodysplastic syndrome. J Clin Oncol. 2021;39(30):3328-3339. doi:10.1200/JCO.20.03380
3. Penack O, Peczynski C, Mohty M, et al. How much has allogeneic stem cell transplant-related mortality improved since the 1980s? A retrospective analysis from the EBMT. Blood Adv. 2020;4(24):6283-6290. doi:10.1182/bloodadvances.2020003418
4. Artz A, Logan BR, Saber W, et al. The Composite Health Risk Assessment Model (CHARM) to predict 1-year non-relapse mortality (NRM) among older recipients of allogeneic transplantation: a prospective BMT-CTN study 1704. Presented at: ASH 2023; December 9-12, 2023; San Diego, CA. Abstract 109.
5. Sung AD, Koll T, Gier SH, et al. Preconditioning frailty phenotype influences survival and relapse for older allogeneic transplantation recipients. Transplant Cell Ther. 2024;30(4):415.e1-415.e16. doi:10.1016/j.jtct.2024.01.062
6. Derman BA, Kordas K, Ridgeway J, et al. Results from a multidisciplinary clinic guided by geriatric assessment before stem cell transplantation in older adults. Blood Adv. 2019;3(22):3488-3498. doi:10.1182/bloodadvances.2019000790
7. Mohile SG, Mohamed MR, Xu H, et al. Evaluation of geriatric assessment and management on the toxic effects of cancer treatment (GAP70+): a cluster-randomised study. Lancet. 2021;398(10314):1894-1904. doi:10.1016/S0140-6736(21)01789-X
8. Li D, Sun C-L, Kim H, et al. Geriatric Assessment-Driven Intervention (GAIN) on chemotherapy-related toxic effects in older adults with cancer: a randomized clinical trial. JAMA Oncol. 2021;7(11):e214158. doi:10.1001/jamaoncol.2021.4158
9. Puts M, Alqurini N, Strohscein F, et al. Impact of geriatric assessment and management on quality of life, unplanned hospitalizations, toxicity, and survival for older adults with cancer: the randomized 5C trial. J Clin Oncol . 2023;41(4):847-858. doi:10.1200/JCO.22.01007
10. DuMontier C, Uno H, Hshieh T, et al. Randomized controlled trial of geriatric consultation versus standard care in older adults with hematologic malignancies. Haematologica. 2022;107(5):1172-1180. doi:10.3324/haematol.2021.278802

BrECADD Regimen Reaches “Unprecedentedly High” PFS in Hodgkin Lymphoma, Reduces Toxicities

When PET is used to guide treatment of brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD) after 2 cycles, the regimen is significantly more effective than bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) in patients with advanced stage Hodgkin lymphoma, according to results presented by Peter Borchmann, MD, of University Hospital of Cologne, the Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf, and the German Hodgkin Study Group during a presentation at the 2024 American Society of Clinical Oncology Annual Meeting.¹

Peter Borchmann, MD | Image credit: University Hospital of Cologne

The findings, according to Borchmann, challenge the standard of care of escalated BEACOPP (eBEACOPP) for these patients. Introduced 2 decades ago, eBEACOPP improved progression-free survival (PFS) and overall survival (OS) through the reduction of primarily progressive disease or early relapse,² the so-called “hit it hard and early” principle, he explained. Patients who were at higher risk of treatment failure benefited the most from this approach, but the risk for acute and persisting toxicities increased for all patients.

“That’s why the overall risk-to-benefit ratio of this approach was questioned,” Borchmann said. However, because of the high efficacy of eBEACOPP, PET was able to guide treatment and reduce intensity from 8 to only 4 cycles for most patients.³ The goal of the HD21 study was to improve on the treatment strategy by modifying the eBEACOPP regimen with brentuximab vedotin, which has a better risk-to-benefit profile than conventional chemotherapy, he noted.

BrECADD maintains the backbone of doxorubicin, cyclophosphamide, and etoposide, but brentuximab vedotin replaced bleomycin and vincristine, dacarbazine replaced procarbazine, and 4 days of dexamethasone replaced 14 days of prednisone.

In the final analysis of an international, randomized, phase 3 HD21 trial of nearly 1500 patients with a median follow-up of 48 months, BrECADD achieved an “unprecedentedly high” 4-year progression-free survival rate of 94.3%, he said. Most (64%) patients received only 4 cycles of treatment, which equals a treatment duration of 12 weeks. The trial had a co–primary end point of reducing toxicity and improving PFS.

A total of 742 patients received BrECADD and 740 received BEACOPP. In the trial, the median age was 31.1 years (range,18 to 60) and 44% were female. For 57.5% of patients receiving BrECADD and 58.2% of patients on BECAOPP, PET after 2 cycles (PET2) was negative and they were scheduled to receive 4 treatment cycles.

At the interim analysis, 1 year ago, BrECADD was shown to be noninferior to BEACOPP, and at the final analysis being presented in 2024, BrECADD was found to be superior, Borchmann said. The overall 4-year PFS was 94.3% for BrECADD (95% CI, 92.6-96.1) compared with 90.9% for BEACOPP (95% CI, 88.7-93.1) Among patients who were PET2-negative, the 4-year PFS was 96.5% for BrECADD. The 4-year OS for these patients was 98.5% for BrECADD and 98.2% for BEACOPP.

Borchmann explained that BrECADD was better tolerated than escalated BEACOPP. The risk for acute and severe toxicities was reduced to 0.72 and more than 99% of patients had a resolution of these treatment-related morbidities at the 12-month follow-up. The recovery rate at 1 year is important for the population being treated, he noted.

“These patients are very young, and they face a life-threatening diagnosis,” Borchmann said. “So they would accept treatment-emerging adverse events as long as they are primarily cured and as long as these adverse events would then disappear over time.”

The reduction of severe and acute toxicities was observed for all subgroups. Patients on BrECADD also had a clinically highly relevant reduction of neuropathy and gonadal dysfunction, he said.

“Due to this very favorable risk-benefit profile, we recommend individualized, PET2-guided BrECADD as the standard treatment option for advanced stage classic Hodgkin lymphoma in this patient cohort,” Borchmann concluded.
This study was funded by Takeda.

References
1. Borchmann P, Moccia AA, Greil R, et al. Tolerability and efficacy of BrECADD versus BEACOPP in advanced stage classical Hodgkin lymphoma: GHSG HD21, a randomized study. Presented at: ASCO 2024; May 31-June 4, 2024; Chicago, Illinois. Abstract LBA7000.
2. Diehl V, Franklin J, Pfreundschuh M, et al; the German Hodgkin Study Group. Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin’s disease. N Engl J Med. 2003;348(24):2386-95. doi:10.1056/NEJMoa022473
3. Borchmann P, Goergen H, Kobe C, et al. PET-guided treatment in patients with advanced-stage Hodgkin’s lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group. Lancet. 2017;390(10114):2790-2802. doi:10.1016/S0140-6736(17)32134-7

Epcoritamab Plus Rituximab and Lenalidomide Shows Deep Responses in Untreated Follicular Lymphoma

Patients with follicular lymphoma treated with first-line epcoritamab plus rituximab and lenalidomide showed deep, durable responses in the EPCORE NHL-2 study (NCT04663347), according to a poster presented at the 2024 American Society of Clinical Oncology Annual Meeting.¹

The analysis included results from arm 6 of EPCORE NHL-2, which evaluated epcoritamab in combination with rituximab and lenalidomide in 41 patients with previously untreated follicular lymphoma, and arm 7 of the study, which assessed maintenance single-agent epcoritamab given every 8 weeks among 20 patients with follicular lymphoma in complete response (CR) or partial response (PR) after 1 to 2 lines of standard of care therapy.

“In first-line follicular lymphoma, more effective, less toxic treatment options that induce durable complete responses are needed,” the authors wrote. “For responders, novel maintenance approaches are needed to improve long-term outcomes.”

In arm 6 of the study, patients received up to twelve 28-day cycles of rituximab and lenalidomide, plus subcutaneous epcoritamab once weekly for cycles 1 and 2, then every 4 weeks from cycle 3 to cycle 26. Patients in arm 7 received epcoritamab once weekly for cycle 1, then every 8 weeks from cycles 2 through 13, with 56 days per cycle. The main end points were overall response rate (ORR) and safety/tolerability in arms 6 and 7, respectively.

To mitigate the risk of cytokine release syndrome (CRS), patients received step-up dosing of epcoritamab as well as corticosteroid prophylaxis during cycle 1 of treatment.

Frontline Epcoritamab Combination Shows Durable Efficacy in Follicular Lymphoma
At the data cutoff of November 22, 2023, a total of 41 patients in arm 6 of the study had received first-line epcoritamab plus rituximab and lenalidomide, and the combination showed deep, durable efficacy.

At a median follow-up of 21.1 months, the ORR and CR were 95% and 85%, respectively, in arm 6. Furthermore, an estimated 90% of patients were alive and progression free at 18 months. Safety was consistent with prior data, and the most common treatment-emergent adverse events (TEAEs) were COVID-19, CRS, and neutropenia, which occurred in 63%, 56%, and 56% of patients, respectively.

CRS mainly occurred during cycle 1, and CRS events were low grade. Overall, 17 patients (41%) experienced grade 1 and 6 patients (15%) experienced grade 2 CRS, and no participants discontinued epcoritamab treatment due to CRS.

Joshua Brody, MD | Image credit: Mt. Sinai

“The results from this preliminary analysis of epcoritamab in combination with rituximab-lenalidomide as a first-line, chemotherapy-free treatment for patients with [follicular lymphoma] are encouraging and support the continued evaluation of epcoritamab in this patient population,” Joshua Brody, MD, director of the Lymphoma Immunotherapy Program at Icahn School of Medicine at Mount Sinai Hess Center for Science and Medicine, said in a statement.²

Maintenance Epcoritamab Well Tolerated in Follicular Lymphoma
By the data cutoff, 20 patients in arm 7 had received epcoritamab maintenance while in CR (n = 12) or PR (n = 8) after 1 to 2 lines of standard therapy.1 Median follow-up was 19.7 months, and 60% of patients experienced CR while 40% experienced PR with their last line of treatment. Overall, 80% of patients (n = 16) had undergone 1 prior treatment and 15% (n = 3) had undergone 2 lines of standard of care treatment.

All patients who enrolled with PR converted to CR on epcoritamab maintenance, and 6 of 8 conversions to CR happened by the first assessment at week 12 of the study. At 21 months, an estimated 83% of patients remained in response and 90% were alive.

The most common TEAEs, COVID-19 and CRS, occurred in 70% and 55% of patients, respectively. Regarding CRS, 40% of patients (n = 8) experienced grade 1 and 15% (n = 3) experienced grade 2 events. Most cases occurred after the first full dose of epcoritamab, and all cases resolved. The only fatal TEAE was respiratory failure linked to post–acute COVID-19 syndrome after 2 treatment cycles.

AT PRESS TIME: On June 26, 2024, FDA granted accelerated approval to epcoritamab for use in treating adults with relapsed or refractory follicular lymphoma after at least 2 lines of systemic therapy. The decision is supported by data from the EPCORE NHL-1 trial. Full coverage will appear in the August issue of Evidence-Based Oncology.

References
1. Lori LA, Falchi L, Vermaat JSP, et al. Epcoritamab with rituximab + lenalidomide (R2) in previously untreated (1L) follicular lymphoma (FL) and epcoritamab maintenance in FL: EPCORE NHL-2 arms 6 and 7. J Clin Oncol. 2024;42(suppl 16):7014. doi:JCO.2024.42.16_suppl.7014
2. Preliminary analysis of data evaluating investigational epcoritamab (Duobody CD3xCD20) combination demonstrates 95% overall response rate in patients with previously untreated follicular lymphoma. News release. Genmab. June 2, 2024. Accessed June 14, 2024. https://www.businesswire.com/news/home/20240602990089/en/Preliminary-Analysis-of-Data-Evaluating-Investigational-Epcoritamab-DuoBody%C2%AE-CD3xCD20-Combination-Demonstrates-95-Overall-Response-Rate-in-Patients-with-Previously-Untreated-
Follicular-Lymphoma

Formulary Switch From Ibrutinib to Zanubrutinib Yields Positive Safety, Efficacy Data

Zanubrutinib (Brukinsa; BeiGene) leukemia and small lymphocytic leukemia, according to real-world results presented at the 2024 appears safe and effective, with lower cardiotoxicity rates than ibrutinib, for patients with chronic lymphocytic American Society of Clinical Oncology (ASCO) Annual Meeting.¹ The abstract focused on a community oncology practice that switched up its formulary to encourage use of the next-generation Bruton tyrosine kinase (BTK) inhibitor.

A bevy of clinical trials have revealed zanubrutinib’s edge over ibrutinib in terms of top-line outcomes, notably the ALPINE trial (NCT03734016), which at 39 months showed a 32% progression-free survival advantage for the former, with benefits sustained even for the highest-risk patients.² Experts attribute this edge to an improved mechanism of action that offers higher concentration ratios and fewer off-target effects. However, it is also essential to supplement the knowledge base on zanubrutinib’s use in the real world as it makes its way onto more treatment guidelines and formularies.

Adding to this evidence are the data presented at ASCO 2024 showing treatment patterns and outcomes after a formulary switch.1 The investigators collected data on patients treated at Kaiser Permanente Northern California, an integrated oncology practice that replaced ibrutinib with zanubrutinib on its formulary. According to the abstract, these adult patients received at least 3 months of zanubrutinib treatment between October 1, 2018, and September 15, 2023.

Of these 281 patients, 190 had switched from ibrutinib to zanubrutinib and 91 received zanubrutinib only. Most patients were White (75%) and 10% were Black. The ibrutinib-zanubrutinib and zanubrutinib-only groups were comparable in terms of sex, race, and insurance type, although the former group was younger (median age, 69 vs 74 years) and had fewer comorbidities. Median follow-up time was also longer for patients on ibrutinib vs zanubrutinib (median, 46.0 vs 23.7 months).

Both BTK inhibitors yielded similar rates of treatment-emergent adverse events (ibrutinib, 36.3%; zanubrutinib, 31.3%), but zanubrutinib had a lower rate of treatment-limiting adverse events (11.1% vs 7.8%, respectively). The most common events leading to discontinuation were atrial fibrillation and fatigue for ibrutinib and cytopenias and rash/bruising for zanubrutinib.

Dose modification, primarily caused by grade 1 or 2 adverse events, occurred in 34 patients on ibrutinib and 50 patients taking zanubrutinib. In the zanubrutinib group, 79% remained on treatment as of the end of data collection; among the 13 patients in this group who died, no deaths were related to treatment.

Of particular interest for the investigators were cardiac adverse events, as the BTK inhibitor class caries some risk of cardiotoxicity, with fewer cardiac events seen with the second-generation drugs including zanubrutinib.2 The data from Kaiser Permanente Northern California were consistent with this trend, as cardiac events—both treatment limiting and otherwise—were more common with ibrutinib than zanubrutinib (treatment limiting, 8 [4.2%] vs 2 [0.7%]; non–treatment limiting, 18 [9.5%] vs 6 [2.1%]).¹

The investigators concluded that despite the shorter follow-up time available for their zanubrutinib group, these results confirm the safety and efficacy of zanubrutinib in the real world for patients with and without prior ibrutinib treatment.

References
1. Krackeler M, Chee B, Orchanian AK, et al. Real-world treatment patterns and outcomes of zanubrutinib in chronic lymphocytic leukemia and small lymphocytic leukemia (CLL/SLL). J Clin Oncol. 2024;42(suppl 16):11158. doi:10.1200/JCO.2024.42.16_suppl.11158
2. Caffrey M. ALPINE: after 39 months, zanubrutinib keeps its PFS edge over ibrutinib in R/R CLL, especially for high-risk patients. The American Journal of Managed Care. December 9, 2023. Accessed June 11, 2024. https://www.ajmc.com/view/alpine-after-39-months-zanubrutinib-keeps-its-pfs-edge-over-ibrutinib-in-r-r-cll-especially-for-high-risk-patients

SPOTLIGHT: Tycel Phillips, MD, on Glofitamab in MCL: “Durability of Response” With Greater Access

Glofitamab, a bispecific T-cell engager, is currently being investigated in a phase 1/2, multicenter, open-label, dose-escalation study (NCT03075696) as monotherapy and in combination with obinutuzumab, a humanized anti-CD20 antibody, following 1-time fixed-dose pretreatment with obinutuzumab.¹

Sold as Columvi by Roche, glofitamab targets CD20 and CD3 and is currently approved to treat large B-cell lymphoma.²

Tycel Phillips, MD | Image credit: City of Hope

An interim analysis of this trial was presented June 1, 2024, at the 2024 American Society of Clinical Oncology Annual Meeting by Tycel Phillips, MD, associate professor, Division of Lymphoma, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, in the oral abstract session, “Hematologic Malignancies—Lymphoma and Chronic Lymphocytic Leukemia.”

Data in his abstract, “Glofitamab monotherapy in patients with heavily pretreated relapsed/refractory (R/R) mantle cell lymphoma (MCL): updated analysis from a phase I/II study,” show that most patients with heavily pretreated relapsed/refractory MCL, a rare type of B-cell non-Hodgkin lymphoma, with a complete response at the end of therapy were alive and progression free at 15 months after therapy ended.³

This interview with Evidence-Based Oncology (EBO) is lightly edited for length and clarity.

EBO: Can you discuss the importance of these findings for patients with MCL previously refractory to a Bruton tyrosine kinase (BTK) inhibitor?

Phillips: In the short term, the thing that’s beneficial for patients is that in this post-BTK space, we have very limited options for durability. For the most part, we are shifting from treatment to treatment in a majority of these patients outside the chimeric antigen receptor [CAR] T-cell therapy, brexucabtagene autoleucel [brexu-cel]. Because glofitamab can be given in a clinical setting—it doesn’t necessarily have to be given in a CAR T or transplant center—it does, in this situation, give some hope that we can have some durability of response, that we’ll have greater access to patients and not require them to necessarily uplift or greatly alter their lifestyle, or life, to get a treatment to get some durability of response.

So again, encouraging early findings. We do need more long-term maturation of the clinical data in order to get a true sense of how doable these responses are. But from this, this most recent update is still very encouraging for this patient population, where there are very little
treatments available for patients.

EBO: What are some advantages of giving patients this fixed-duration treatment?

Phillips: By having a fixed duration, first, it does allow for some immune recovery; it allows patients the ability to sort of reconstitute the immune system and reduces some of the risk of long-term infections. Second, you would presume that this would reduce the amount of cost to the medical system because the patient isn’t coming in for an indefinite period of time with blood draws, vitals, etc, and then not to mention the cost of the medication. So going back to your first question, if these responses remain durable, with the treatment duration only being around 8.3 months, it does allow these patients to get an effective therapy, an efficient therapy, and then have some time where they’re not necessarily being bogged down in a medical system and enjoy some quality of life.

EBO: As earlier use of BTK inhibitors becomes more common, is it possible glofitamab outcomes will improve among those who are refractory to BTK inhibitors?

Phillips: It’s a bit speculative. In theory, we always assume the less pretreated the patients are, the more likely they are to respond to certain therapies. I don’t necessarily know if we’ll see a major shift in the efficacy based on whether they get more or less lines of therapy. But historically, that has been the case. If you look at the BTK inhibitors as an example, when they first came out, they were using it in the third-line setting. And then we saw that patients who got those drugs in a second-line setting had a much higher chance of getting a complete response and a durable response. So if that mechanism continues to follow suit with these bispecifics, you will presume that you would get a little bit higher response rate and a little bit more duration of response if it’s given earlier. But I think we would need to see a little bit of a bigger trial just to get that sort of true sense of how the lines of therapy are impacting efficacy of glofitamab.

EBO: Some patients in the study are pretreated with obinutuzumab prior to receiving the bispecific glofitamab. Can you discuss the rationale for this sequencing?

Phillips: The biggest issues with T-cell directed therapy, which includes bispecifics or CAR T-cell therapy, are cytokine release syndrome, or CRS, or immune cell affecting neurological syndromes, which is ICANS. To help mitigate some of these [adverse] effects, bispecifics are given in what we call a step-up dosing fashion, meaning we start with a small dose—in this case, 2.5 mg—and then the next week escalate to 10 mg and [then] 30 mg.
As an extra step to help reduce some of these events, especially cytokine release syndrome, glofitamab is given with an obinutuzumab pretreatment.

This is a competitive sort of situation—the obinutuzumab binds in a very similar region or same location as glofitamab. Because of this, when these patients are getting the initial dose of glofitamab, there is still obinutuzumab binding to the cancer cell and also the normal B cells. So you get some competitive binding, which reduces the rates and risk of CRS and allows the body to get more acclimated to the drug. Then when you get the next dose at 10 mg, you don’t really have that competitive binding, but hopefully at that point, the body has already adjusted to the medication.

And just from what we’ve seen clinically, the rates of CRS are much less from the first dose of 2.5 mg, down to the 10-mg dose, and then even less with a 30-mg dose. As an aside, especially at least in mantle cell lymphoma, the good thing is while we get a lot of that competitive binding with a 2.5-mg dose because of how fast the body clears obinutuzumab, it’s not much [left] with a 10-mg or 30-mg dose.

EBO: In terms of sequencing these therapies, what do we know about having options available ahead of or after CAR T-cell therapy?

Phillips: It’s a little hard because we just don’t have the data in mantle cell lymphoma that we have in some of the other diseases, [such as] large B-cell lymphoma. I think there are quite a bit of data about bispecifics after CAR T, and we’re starting to get some early data about bispecifics before CAR T. We don’t really have that information with patients who have mantle cell lymphoma. Presumably because the targets are a little bit different—bispecifics are targeted at CD20; CAR T is targeting CD19—we are likely not to have any sort of detrimental impact by using one before the other. Or so in that situation, I don’t think there will be any harm, to the point where if CAR T is a bit limited, because patients have to go to CAR T centers (and they have to be in those centers for around 14 days), at least some patients refuse that or they just don’t have access to a CAR T center. The fact that glofitamab does not require a specific center, that you don’t have to have a specific designation to get it—the center just has to be able to basically monitor the patients for up to 24 hours and sometimes a little bit longer for the [adverse] effects. It does allow glofitamab to be given in a wider range of clinical settings.

Additionally, glofitamab is an antibody so it does not require any real manufacturing process. So sometimes the time delay that you have from getting insurance approval, to getting cell collection, to cell manufacturing cell return—you don’t necessarily run into those issues with these bispecific antibodies. It is literally off the shelf; you get approval, you put in an order, and the drug is given. So that does allow a little bit more of speed of access.

One other point: CAR T in large cell lymphoma is thought to be a curative treatment. We don’t necessarily have that information in mantle cell lymphoma. And at least from what we see from the early clinical data, it probably suggests that brexu-cel is not going to be a curative treatment for the vast majority of patients with mantle cell lymphoma. In that regard, it does open up more avenues to consider other treatments if the duration of response is relatively equivalent, and that doesn’t take into account the safety differences between the 2 treatments.

EBO: Is there anything that we didn’t cover that you’d like to add?

Phillips: For patients with mantle cell lymphoma, at least, if this works out, it gives us another treatment option for this patient population. Hopefully, this will expand the access to these patients to get a treatment that is potentially durable, and one that, depending on how long they get a response, does allow for these patients to potentially be retreated with this drug. So we may be having a discussion several years down the line, not just including the initial response but also the second response, and how long that lasts and how long in total we are able to keep these patients in remission and hopefully get these patients to have some enjoyable quality of life.

References
1. A dose escalation study of glofitamab (RO7082859) as a single agent and in combination with obinutuzumab, administered after a fixed, single pre-treatment dose of obinutuzumab in participants with relapsed/refractory B-cell non-Hodgkin’s lymphoma. ClinicalTrials.gov. Updated May 14, 2024. Accessed June 1, 2024. https://clinicaltrials.gov/study/NCT03075696
2. FDA approves Roche’s Columvi, the first and only bispecific antibody with a fixed-duration treatment for people with relapsed or refractory diffuse large B-cell lymphoma. News release. Roche. June 16, 2023. Accessed June 11, 2024. https://bit.ly/4aTxibC
3. Phillips TJ, Carlo-Stella C, Morschhauser Fanck, et al. Glofitamab monotherapy in patients with heavily pretreated relapsed/refractory (R/R) mantle cell lymphoma (MCL): updated analysis from a phase I/II study. Presented at: ASCO 2024; May 31-June 4, 2024; Chicago, IL. Abstract 7008. https://meetings.asco.org/2024-asco-annual-meeting/15770