Brentuximab: ASH 2022 Dr. Mitul Gandhi Updated Efficacy and Safety Results
By Mitul Gandhi, MD
What were the results of the safety and efficacy of Brentuximab brand name ADCETRIS, in patients with Hodgkin Lymphoma? So this is a multi-center, multi-part study. Taking patients in this particular part B, evaluating patients with stage 2 bulky hodgkin’s lymphoma and stage 3 and 4 hodgkin lymphoma.
The existing standard of care represents a combination of ABVD Adriamycin, Bleomycin, Vinblastine, Dacarbazine, often with omission of Bleomycin after PET stratification after cycle 2. Along with the newer standard of care based on the ECHELON-1 data which is a combination of Brentuximab with Adriamycin, or Doxorubicin, Vinblastine, and Dacarbazine.
So that represents this existing standard of care. This current trial is evaluating a novel combination and leveraging the activity of 2 the more potent agents that have already been used in the relapse setting. Nivolumab, which is a checkpoint inhibitor leveraging the immune system and it’s ability to treat hodgkin’s lymphoma and the well-known monoclonal antibody drug conjugate Brentuximab, bringing them in the frontline setting along with a taper-down cytotoxic backbone.
So this particular study is looking at Nivolumab plus Brentuximab in combination with Adriamycin and Dacarbazine in stage 2 bulky and stage 3, stage 4, hodgkin’s lymphoma.
What is the current standard of care for Hodgkin Lymphoma?
The standard of care currently still represent, is represented by combination ABVD Doxorubicin, Vinblastine, rather Bleomycin, Vinblastine and Dacarbazine, or the AAVD regimen as studied in ECHELON-1 with Brentuximab, Adriamycin, Vinblastine, Dacarbazine. That is the existing standard of care, and this is a novel regimen leveraging checkpoint inhibition plus Brentuximab in a frontline setting.
What is the trial design and why was it set up this way?
So the way this study was conducted was a open label phase 2 multi-part study and Nivolumab and Brentuximab along with Doxorubicin and Dacarbazine were given on day 1 and day 15 every 28 days. This is a combination that with each of the drugs that had been most studied and represents the most rationale regimen patients were given this combination up to 6 cycles with a primary objective of a response. And that’s how the regimen was studied.
What is Brentuximab Vedotin?
The injections of brentuximab are used to treat the blood malignancies Hodgkin lymphoma, systemic anaplastic large cell lymphoma (sALCL), and primary cutaneous anaplastic large cell lymphoma (pcALCL). It is administered to patients who have received an unsuccessful bone marrow (autologous stem cell) transplant or other cancer treatments.
Brentuximab Vedotin injection is also used in conjunction with other cancer drugs (e.g., doxorubicin, vinblastine, dacarbazine) to treat untreated stage III or stage IV classical Hodgkin lymphoma.
In patients with previously untreated sALCL or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL, are also treated with Brentuximab injection in combination with other drugs (e.g., cyclophosphamide, doxorubicin, prednisone).
Brentuximab inhibits the growth of cancer cells, which are subsequently eliminated by the body.
This medication should only be administered by or under the direct supervision of your physician for your cancer type (e.g. angioimmunoblastic T-cell lymphoma).
This medication is offered in the following dose forms, Powder for Remedy.
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What are some of the significant data and statistics for the Brentuximab clinical trials for patients with hodgkin lymphoma?
I think the take home data points are a response rate of 93% and a complete response rate of 88% with a manageable toxicity profile. There was approximately 50% treatment emergent adverse events that were noted. The most prominent being fatigue, nausea, and sensory peripheral neuropathy. although only a small minority really had treatment related sensory peripheral neuropathy.
Key Takeaways from the Brentuximab Clinical Trial in Patients with hodgkin lymphoma
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In Part B of SGN35027, therapy with BV, nivolumab, doxorubicin, and dacarbazine (AN+AD) shown encouraging preliminary activity in patients with bulky stage II or stage III/IV cHL (at EOT: ORR 93%; CR 88%) without febrile neutropenia or adverse events (AEs) of grade 5. (Lee 2021). Part B of this study’s updated efficacy and safety results are presented here.
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SGN35027 is an open-label, phase 2 clinical trial with various parts and multiple centers. Patients recruited in Part B had Ann Arbor stage I or II cHL with bulky mediastinal disease (defined as 10 cm) or stage III or stage IV cHL. Up to 6 cycles of AN+AD (BV 1.2 mg/kg [A], nivolumab 240 mg [N], doxorubicin 25 mg/m2 [A], and dacarbazine 375 mg/m2 [D]) were administered to patients. On Days 1 and 15 of each 28day cycle, all study medications were delivered intravenously. Primary outcome measure was CR rate at EOT. Safety, tolerability, ORR, duration of objective response (DOR), duration of complete response (DOCR), and progression-free survival (PFS) were important secondary goals.
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There were 58 patients enrolled in Part B, of which 57 got at least one dosage of the experimental medication. The majority of patients treated were white (88%) and under 65 years old (95%) and over half are male (53%). 35 years was the median age (range: 19, 78 years). 30% of treated patients had stage II cHL with substantial mediastinal disease, whereas the remaining patients had stage III (18%) or stage IV (51%). At EOT, the total CR rate among the 57 patients treated was 88% (95% CI: 76.3, 94.9) EOT ORR (complete response [CR] or partial response [PR]) was 93% (95% CI: 83.0, 98.1) With a median followup of 15,1 months, four patients (7%) had progressive disease, and one patient (2%) passed away. At 12 months, the estimated PFS rate was 93% (95% CI: 81.6, 97.2) As of the data cutoff date (02May2022), 93% (95% CI: 81.7, 97.2) of patients had a DOR of at least 12 months, whereas 92% (95% CI: 80.0, 96.9) of patients had a DOCR of at least 12 months.
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AN+AD remains a potential treatment for adult patients with bulky stage II or stage III/IV cHL, according to efficacy data. Updated safety results indicate that AN+AD continues to be tolerable, and no new safety signals have been observed. It is possible that omitting bleomycin and vinblastine contributed to the lack of certain adverse events, such as febrile neutropenia. This investigation is ongoing, and revised findings will be presented.
Did this trial have a primary endpoint, and was it met?
Primary endpoint was assessing efficacy and overall response rate. And this was demonstrated with the aforementioned 88% complete remission rate and the 93% overall response rate. And the safety data, which is still being accumulated but shows the about 50% treatment emergent grade 3 and above toxicity. Noteworthy, other safety points with some of the endocrinopathy scene, which is common with checkpoint inhibition therapy along with the cutaneous toxicity,
What are the most common questions for the Brentuximab research?
I think the most common question is being asked, which was one of the rationales was this, of this study was when are we going to be able to take these other very effective agents used in the salvage setting, but moving them frontline? And this study represented that a very important step in that approach, most of us, are very aware of the activity of these other drugs in a relapse setting and trying to get them earlier on, minimizing toxicity from chemotherapy and still achieving durable, long-term responses. So I think that’s probably the first question that’s asked.
The second is, of course, safety. Expanding on many of the known effects of these agents, particularly, what is the rates of peripheral sensory neuropathy on Brentuximab, which is a well-known side effect, allergic reaction or allergic reactions (e.g. skin rash, trouble breathing, dark urine, acute pancreatitis, toxic epidermal necrolysis, vision changes, dry skin), along with immune mediated toxicities from Nivolumab. And this does give us a data set as a benchmark to show what the expected toxicities are.
What are the key takeaways from the Brentuximab research and data?
I think what this represents is an important first step showing that tapering down the cytotoxic therapy backbone and combining novel agents up front is still able to elicit a very high complete response rate. And does raise a prospect of combining it with the existing standard of care to demonstrate non-inferiority and perhaps superiority with less chemotherapy targeted compounds upfront achieving a impressive long-term survival while trying to pair down on short and long-term toxicity. So I think it’s going to invite the next iteration of studies looking at these combination against the existing standard of care.
Mitul Gandhi, MD – About The Author, Credentials, and Affiliations
Mitul Gandhi, MD, received his Bachelor of Arts degree in Molecular Biology and Biochemistry from Rutgers University. He acquired his medical degree from Rutgers Robert Wood Johnson Medical School, where he was honored with the Robert Wood Johnson Foundation Research Award, among other accolades. Dr. Gandhi then finished his internal medicine residency and internship at the University of Michigan Health System. He is working at the Virginia Cancer Specialists which is a part of the US Oncology Network.
Dr. Gandhi joins Virginia Cancer Specialists after serving as Chief Fellow in Northwestern University Feinberg School of Medicine’s Medical Oncology and Hematology Fellowship program. Dr. Gandhi actively involved in clinical research at Northwestern, with a focus on high-risk lymphoma. He has presented at various national meetings, received the Abstract Achievement Award from the American Society of Hematology in 2013, and has multiple publications, including a recent work in Blood on double hit lymphomas. Dr. Gandhi is a member of the American Society of Hematology as well as the American Society of Clinical Oncology.
Reference
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Mayo Clinic – Brentuximab (Intravenous Route). Mayo Clinic, January 21, 2023
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ASH – 314 Brentuximab Vedotin, Nivolumab, Doxorubicin, and Dacarbazine (AN+AD) for Advanced Stage Classic Hodgkin Lymphoma: Updated Efficacy and Safety Results from the Single-Arm Phase 2 Study (SGN35-027 Part B). ASH, December 10, 2022