EHA's joint creation of the future, the study and interpretation of the three combination regimens of gefituzumab, entering the era of "lighter, stronger, and higher" B-NHL treatment
Editor's note: In June, a series of international events were held to showcase the latest excellence in the field of hematology-oncology. A number of clinical studies of the CD20/CD3 bispecific antibody Glofitamab have been successfully selected for the 2024 ASCO and 2024 EHA Annual Meetings, which not only demonstrates its outstanding demeanor and solid strength on the international stage, but also highlights the broad prospects and unlimited potential of gefituzumab in the field of B-NHL treatment. Professor Li Zhiming from the Cancer Prevention and Treatment Center of Sun Yat-sen University and Professor Li Zengjun from Shandong Cancer Hospital are specially invited to give an in-depth interpretation of these studies, in order to provide readers with cutting-edge progress in the field of lymphoma.
As the first IgG1-like fully humanized CD20/CD3 bispecific antibody in China, gefituzumab is unique in that it contains two CD20-binding domains and one CD3-binding domain. This innovative 2:1 structure design is designed to significantly enhance the targeting of CD20-positive lymphoma cells and exert anti-tumor effects by redirecting CD3 effector T cells to the surface of tumor cells or adjacent regions. This design not only gives geflexumab excellent therapeutic potential, but also has far-reaching clinical application value, which has demonstrated remarkable efficacy in patients with relapsed and refractory diffuse large B lymphoma (R/R DLBCL), and has been successfully approved in China for the treatment of adult patients with R/R DLBL who have received at least 2 prior lines of systemic therapy. Recently, gefituzumab announced a number of latest research progress on combination therapy, indicating that its future application prospects will be further broadened and is expected to bring good news to more patients.
Synergies
BTKi dances with TCE to refresh the R/R DLBCL treatment landscape
Despite the significant success of various therapeutic approaches in improving the prognosis of patients with DLBCL, a significant proportion of patients are still at risk of progressing to R/R DLBCL.1 As a disease involving multiple signaling pathways2, the treatment of R/R DLBCL is relatively complex, and the prognosis of patients is not ideal because there is no unified standard treatment regimen. In order to improve the current treatment status and improve the treatment effect, there is an urgent need to explore and develop new treatment strategies. In vitro studies have shown a synergistic effect between T cell engagers (TCEs) and BTK inhibitors (BTKi)1, and this combination is expected to bring breakthrough advances in the therapeutic field of R/R DLBCL. At the 2024 ASCO Annual Meeting, a multicenter, open-label, single-arm Phase II clinical study (NCT05335018) presented its interim analysis (Abstract No. 7066)1, fully demonstrating the excellent efficacy and favorable safety performance of gefituzumab + poseltinib + lenalidomide (GPL regimen) in the patient population with R/R DLBCL.
Study design
The study plans to enroll 76 patients with R/R DLBCL who do not respond to first-line therapy or have failed ≥ 2nd line of therapy. Patients who have received prior CD19 CAR-T therapy are allowed, but patients who have received prior CD20 TCE therapy are excluded. All patients were dosed with escalating doses of gefituzumab from 2.5 mg to 10 mg in Cycle 1 and 30 mg in Cycle 2 D1 and beyond. Lenalidomide (D1-14, 20 mg, QD) and poseltinib (D1-21, 40 mg, BID) are cycled in 1 cycle every 3 weeks. A total of 12 cycles of induction therapy were followed by 17 cycles of poseltinib and lenalidomide maintenance therapy. The primary endpoint is overall response rate (ORR), with secondary endpoints including duration of response (DoR), complete response rate (CRR), progression-free survival (PFS), overall survival (OS), and incidence of treatment-related adverse events (TEAEs).
Figure 1. Induction therapy regimens
Figure 2. Holistic treatment options
Baseline characteristics
As of November 2023, a total of 37 patients have been treated with GPL, with a median age of 71 years (range: 67~75 years). Thirteen patients (35.1%) had received ≥ 2nd line of therapy, and 26 patients (70.3%) had Ann Arbor stage III./IV. Twenty-one patients (58.6%) had disease recurrence within 1 year. Three patients (7%) had received prior CAR-T therapy.
efficacy
The median follow-up was 3.6 months, with an ORR of 89.3% and a CRR of 42.9% among 28 patients with evaluable efficacy. PFS rates were 81 and 55 percent at 3 and 6 months, OS rates were 91 and 81 percent at 3 and 6 months, and DOR was 94 and 66 percent at 3 and 6 months, respectively (Figure 3). Compared to the first interim results, the ORR increased from 85.7% to 89.3% and the CRR increased from 35.7% to 42.9%. Of the 18 patients, 5 (27.8%) successfully transitioned from initial PR to CR.
图3. OS、PFS、DOR曲线
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The TEAE data for the GPL-covered scheme showed a similar pattern to that of gefintumab, with no safety signals observed in the safety cohort (n=6, 3+3 design), and only 3 patients (8.1%) discontinued GPL-covered treatment due to TEAE. Due to the high number of COVID-19 infections, neutropenia (45.9%) and infection (37.8%) were the most common grade 3/4 TEAEs. The main side effect of gefituzumab was cytokine release syndrome (CRS), with seven patients (18.9%) in the study developing CRS, of whom only two (5.4%) had grade 3/4. Compared with gefituzumab alone, the incidence of CRS was significantly reduced with the GPL-based regimen. In addition, the side effects of BTKi should not be ignored, among which atrial fibrillation and bleeding are considered to be the most serious TEAEs. In this study, only one patient experienced such serious side effects.
Figure 4. Comparison of AEs of the GPL regimen with gefituzumab
This interim analysis suggests that the GPL regimen is expected to be an effective and safe new treatment option for R/R DLBCL. CRR is on the rise as treatment progresses, and it is expected to eventually reach a high level of around 60%. In addition, the high ORR shown in the results provides strong data support for further exploring the potential synergy between TCE and BTKi in GPL solutions.
The two join forces
格菲妥单抗与Englumafusp Alfa共辟R/R B-NHL治疗新径
In addition to the GPL-covered regimen, the combination of gefituzumab with other new drugs is also of significant value. Englumafusp alfa (CD19/4-1BBL), as an innovative antibody-like fusion protein, can precisely target CD19 on the surface of B cells and 4-1BB on the surface of T cells at the same time, and its combination with gefituzumab has shown strong synergistic effect in preclinical models, laying a solid foundation for further clinical research. At the 2024 EHA Annual Meeting, a first-in-human study of gefintumab, the BP41072 study (NCT04077723, abstract number: S237), attracted attention3. The study is a Phase Ib clinical study of gefintumab in combination with Englumafusp alfa in patients with aggressive R/R B-NHL, and aims to comprehensively evaluate the safety, tolerability, pharmacokinetic/pharmacodynamic (PK/PD) properties and preliminary efficacy of this combination regimen. During the meeting, the final dose escalation data was announced, and the results showed that the combination regimen has a good safety profile and significant efficacy, indicating that it has a very broad clinical application prospect.
Study design
After pretreatment with a single dose of obinutuzumab (GPT, 1000 mg), it was administered in ascending doses of gefituzumab (2.5/10/30 mg) in cycle 1/2. After 1 week, the patient was started on Englumafusp alfa and received two drugs every 3 weeks starting with Cycle 3 D1. The overall duration of treatment lasts up to 12 cycles. During dose escalation, a continuous reevaluation method for controlling drug overdose (mCRM EWOC) was employed. At the same time, the response rate of treatment was evaluated according to Lugano staging criteria.
Figure 5. Study design
Baseline characteristics
As of October 25, 2023, a total of 134 patients with R/R B-NHL have been enrolled. Among them, 83 patients had aggressive R/R B-NHL, including 60 cases of DLBCL, 18 cases of large B-cell lymphoma transformed from follicular lymphoma (trFL), 3 cases of large B-cell lymphoma transformed from other indolent NHL, and 2 cases of grade 3B FL. The dose range of Englumafusp alfa was 0.35~75mg, which did not reach the maximum tolerated dose level. Among all patient populations, the median age was 63 years, 41% were female, 47% had an ECOG score of 1, and more than half (50.6%) had stage IV. The median number of treatment lines was 3 lines (range 1~8 lines), 19.3% of the patients were primary refractory cases, and 49.4% had received CAR-T therapy.
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A total of 134 patients were evaluable for safety across all histological types. Common adverse events included CRS (55.2%), anemia (32.1%), COVID-19 infection (26.9%), and neutropenia (25.4%). Grade 5 AEs were reported in nine patients (6.7%), including 3 for TEAEs. One patient developed grade 5 pneumocystis pneumonia associated with gefituzumab treatment, which was considered a dose-limiting toxicity. CRS occurs mainly in patients treated with gefituzumab at doses of 2.5 mg and 10 mg. Specifically, 48.5% of patients developed grade 1 CRS, and only seven patients (5.2%) developed CRS associated with Englumafusp alfa, all of which were grade 1. No new safety signals were identified during the combination of Englumafusp alfa and gefituzumab.
efficacy
At all doses, CRR and BORR were 57% and 67% for overall patients (2L+, N=83), respectively. CRR and BORR were 66 and 73 percent, respectively, for patients who had received CAR-T therapy (2L+, N = 41), while CRR and BORR were both 77 percent in patients who had received only one prior treatment and had not received CAR-T therapy (N = 13).
PK/PD
Serum concentration data for PK analysis in the included population needed to be from patients who had received at least one dose of Englumafusp alfa and had at least one quantifiable PK measurement. In terms of pharmacodynamics, the expansion of activated and memory CD8+ T cells was observed, while the expansion of terminally differentiated PD1+ CD8+ T cells in blood was limited, a phenomenon associated with the deepening of ctDNA responses over time.
The results of the dose-escalation study of Englumafusp alfa in combination with gefituzumab in patients with R/R B-NHL are a surprising breakthrough in the safety and efficacy of combining TCE with a bispecific antibody-like fusion protein that provides a strong costimulatory signal in patients with B-NHL. This combination is currently undergoing an active dose expansion phase and may further revolutionize the therapeutic field of B-NHL.
Light and healing
R-Pola-Glo轻化疗方案在老年DLBCL一线治疗中的卓越表现
For the field of DLBCL treatment, a cure has always been a common goal for both physicians and patients. However, older patients and patients with more comorbidities tend to be at higher risk of treatment and often require less intensive regimens due to limited vital organ reserves4. Unfortunately, these low-intensity treatments tend to be less effective. Therefore, it is urgent to explore a safe and effective treatment strategy for this population. In this context, the R-Pola-Glo chemo-light chemotherapy regimen consisting of rituximab, vepotuzumab and gefituzumab was developed to provide practical guidance for the therapeutic field of DLBCL. At the 2024 EHA Annual Meeting, a prospective, multicenter, bi-national (Germany/Austria) Phase II trial of R-Pola-Glo (abstract number: P1173) attracted widespread attention to evaluate the use of R-Pola-Glo in treatment-naïve DLBCL patients over 60 years of age who are not candidates for full-dose R-CHOP, as well as in all patients over 80 years of age with DLBCL to explore its safety as first-line therapy and 1-year progression-free survival5. In addition, the study compared the safety data of the R-Pola-Glo regimen with the trial of bendamustine in combination with rituximab (BR) regimen (B-R-ENDA).
Study design
The R-Pola-GLO regimen consists of a steroid pre-treatment phase followed by 12 cycles of treatment (q3w). Cycle 1 regimens consist of rituximab + vepotuzumab and escalating dose of gefituzumab (2.5 mg/10 mg). Treatment with rituximab, vepotuzumab, and a target dose (30 mg) of gefituzumab in cycles 2 to 6. The last 6 cycles were spent on the consolidation phase of gefintumab (30 mg). Since the combination regimen was used for the first time in humans, a safety run-in analysis was performed on the first 10 patients. In addition to updating the safety data of this mild chemotherapy regimen, the safety data of this mild chemotherapy regimen was also compared with the safety data of BR regimen6.
Figure 6. Study design
Baseline characteristics
In the safety lead-in cohort, the median age of patients was 79 years (range 69~81 years), and 70% of them were in the advanced stage with elevated lactate dehydrogenase levels. Extranodal involvement occurred in 40% of patients with an ECOG score of less than 3, and 70% had an International Prognostic Index (IPI) of more than 2.
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As of February 2024, the median follow-up was 8 months. A total of 137 AEs were recorded, including hematological/lymphatic system disorders (25 cases, including neutropenia in 4 patients), infection (17 cases), elevated laboratory indicators (16 cases), and gastrointestinal system disorders (14 cases). Of note, only five patients developed grade 1 CRS, and no higher-grade CRS, polyneuropathy, or immune effector cell-associated neurotoxicity syndrome (ICANS) were reported. Among the 28 serious adverse events, infection and neutropenia/neutropenia fever were the main ones, with 9 and 7 cases being the main ones. Most critically, there were no treatment-related deaths in the study.
Safety comparison with BR regimen
To evaluate the feasibility of the R-Pola-Glo regimen, safety data were compared: patients treated with R-Pola-Glo in the lead-in phase (n=9/10, age-matched; age range: 69 to 80 years) and compared with patients with similar age and IPI distributions in the B-R-ENDA trial (n = 29, age range: 61 to 80 years). Grade 3-5 AEs were comparable to any grade of SAEs in the B-R-ENDA and R-Pola-Glo groups, 20% vs. 21% and 63% vs. 71%, respectively. It is noteworthy that in the R-Pola-Glo scheme, level 5 SAEs did not appear.
In summary, R-Pola-Glo has shown a good and manageable safety profile as a light chemotherapy treatment in the elderly and frail DLBCL patient population. To date, the R-Pola-GLO regimen has shown a similar safety profile in a cohort of patients matched for age and clinical risk in the B-R-ENDA trial. This data update is expected to provide new insights into the treatment of DLBCL, especially when designing personalized treatment plans for elderly and frail patients, and will provide clinicians with important references.
Expert commentary
Professor Li Zengjun
In the therapeutic field of B-NHL, the research results of gefituzumab are endless, bringing encouraging hope to both doctors and patients. Taking the GPL scheme as an example, a median follow-up of 3.6 months has achieved high ORR and CRR, indicating the potential of the scheme to achieve rapid and deep remission. What's more, both ORR and CRR improved compared to the first interim outcome, suggesting that treatment may become more effective over time and with increasing duration of medication. In particular, 5 patients were successfully converted from initial PR to CR, which is a positive sign that even patients who did not achieve CR in the early stages of treatment have the potential to achieve a better response in subsequent treatment. In addition, PFS, OS, and DOR data further confirm the effectiveness of GPL-covered protocols in improving patient survival. Digging deeper into the clinical implications behind these data can be found to be particularly suitable for patients who do not respond to first-line therapy or who have experienced failure of multiple lines of therapy, or will further improve the prognosis of these patients. The safety data showed that the GPL-covered regimen was consistent with the known side effects of gfituzumab, showing good safety performance. It is worth mentioning that the incidence of AEs is even lower than that of gefituzumab monotherapy. Regarding the general concern about the incidence of CRS, according to the available research data, the vast majority of CRS is mild to moderate. At the same time, compared with gefituzumab alone, the incidence of CRS with the GPL regimen also decreased. In the future, this study can focus on the collection and analysis of long-term follow-up data to clarify the long-term survival benefit of treatment, so as to provide strong data support and scientific basis for clinical practice.
With the increasing aging of the population, elderly DLBCL patients, as a high-risk group, are receiving more and more medical attention. They generally tolerate antineoplastic therapy lower due to older age, higher comorbidities, and inadequate reserve, limiting the likelihood of similar survival benefits from previous treatments. The current status quo of treatment is far from satisfying their need to improve quality of life and prolong survival. Therefore, the search for a "light" treatment strategy that can not only ensure the quality of life of patients, but also bring survival benefits has become a key issue to be solved urgently. According to the baseline characteristics of the R-Pola-Glo study, most elderly patients are in advanced stages, with poor status, disease activity, and high prognostic risk. In this context, R-Pola-Glo has shown excellent clinical application potential in elderly DLBCL patients due to its controllable safety and good preliminary efficacy, coupled with a safety performance comparable to that of BR. It is expected that more treatment strategies based on gefintumab will be developed in the future, which will bring tangible benefits to more patients.
Professor Li Zhiming
In addition to the GPL and R-Pola-Glo regimens, another joint study of gefituzumab focused on its combination with Englumafusp alfa. This combination regimen has shown positive results in terms of safety, tolerability, and preliminary efficacy, laying a solid foundation for subsequent in-depth research. From the perspective of efficacy data, regardless of whether patients have received CAR-T therapy before, the response rate showed a positive trend. Of particular concern is the fact that patients who have not yet received CAR-T therapy and who have received only one prior therapy have demonstrated higher response rates after treatment. This finding is extremely important for accurately identifying and identifying potential patient beneficiary groups. The results of the safety analysis showed that despite the adverse events, the overall safety was manageable and that no new safety risks emerged from the combination regimen. We look forward to the data from the follow-up studies of this new combination and hope that it will soon be used in a wider patient population, bringing good news and hope to patients."
Three studies have confirmed that gefituzumab has shown good efficacy when combined with other drugs such as BTKi and antibody-like fusion proteins, which is expected to change the existing treatment paradigm. In terms of safety, the data are also excellent, providing clinicians with confidence and assurance when using these combination regimens. With the further application and promotion of these research results, it is believed that gefintumab will play a more important role in clinical practice in the future.
Bibliography:
1. Ja Min Byun, et al. 2024 ASCO Abstract #7066.
2. Wendan Xu, et al . Blood, 138(13), 1110–1119.
3. Morschhauser F, et al. 2024 EHA Abstract #S237.
4. Zettl et al., Ann Hematol. 2021.
5. Wurm-Kuczera R, et al. 2024 EHA Abstract #P1173.
6. Braulke et al., Hemasphere 2022
Professor Li Zhiming
Sun Yat-sen University Cancer Center, Department of Internal Medicine, Professor, Chief Physician, Doctoral Supervisor
Chairman of the Tumor Immunotherapy Professional Committee of the Chinese Geriatric Health Care Association
Chairman of the Lymphoma Professional Committee of Guangdong Anti-Cancer Association
Chairman of the Professional Committee of Comprehensive Treatment of Head and Neck Tumors of Guangdong Provincial Association of Clinical Medicine
Chairman-elect of the Hematology and Oncology Professional Committee of Guangdong Anti-Cancer Association
Deputy Secretary-General and Standing Committee Member of the Anti-Lymphoma Alliance of the Chinese Society of Clinical Oncology (CSCO).
Member of the Standing Committee of the Lymphoma Professional Committee of the Chinese Anti-Cancer Association
Secretary-General and Standing Committee Member of the Lymphoma Professional Committee of the Chinese Geriatric Health Care Association
Member of the Standing Committee of the Head and Neck Oncology Expert Committee of the Chinese Society of Clinical Oncology (CSCO).
Executive Director of the Youth Council of the Chinese Anti-Cancer Association
Member of the Standing Committee of the Lymphoma Branch of the Chinese Medical Education Association
Prof. Li Zengjun
Director of the Department of Lymphatic Hematology, Shandong Provincial Cancer Hospital, Chief Physician
Vice Chairman of the Oncology and Hematology Committee of the Chinese Anti-Cancer Association
Member of the Hematology and Oncology Committee of the Chinese Anti-Cancer Association; Member of the Slow Shower Working Group; Member of the Follicular Lymphoma Working Group
Member of the Anti-Lymphoma Expert Committee of the Chinese Society of Clinical Oncology (CSCO); Member of CSCO China Autologous Hematopoietic Stem Cell Transplantation Working Group
He is a member of the Lymphatic Disease Professional Committee of the Chinese Medical Education Association
Expert of the expert group of the lymphoma specialty construction project of the Capacity Building and Continuing Education Center of the National Health Commission
He is the chairman-elect of the Lymphoma Committee of Shandong Society of Clinical Oncology
Member of Hematology Branch of Shandong Medical Association
Vice Chairman of the Stem Cell and Cell Application Translational Medicine Committee of Shandong Medical Doctor Association
Vice Chairman of Hematology Branch of Shandong Research Hospital Association
Member of the Tumor Clinical Research Professional Committee of Shandong Provincial Hospital Association
Corresponding editorial board member of Chinese Journal of Hematology
Member of the editorial board of the Chinese Journal of Cancer Prevention and Treatment, Cancer, and Leukemia Lymphoma
He has published more than 50 articles as the first or corresponding author
He is the author of the 2018 edition of the "Guidelines for the Diagnosis and Treatment of Chronic Lymphoproliferative Diseases in China" and the "Chinese Expert Consensus on the Diagnosis and Differential Diagnosis of Chronic B Lymphoproliferative Diseases".