Updated efficacy and safety results from Part C of a phase 2 single-arm trial (SGN35-027; ClinicalTrials.gov identifier: NCT03646123; EudraCT 2020-004027-17) evaluating brentuximab vedotin (Adcetris®; Seagen/Takeda)* in combination with the PD-1 inhibitor nivolumab (Opdivo®; Bristol-Myers Squibb) and standard chemotherapy agents doxorubicin (Adriamycin®) and dacarbazine (DTIC-Dome®/Imidazole) for the frontline treatment of patients with early-stage classical Hodgkin lymphoma (cHL), shows that the treatment regimen was all tolerated.

The study outcomes also demonstrated that the treatment combination resulted in fewer than half of patients developing primarily low-grade peripheral neuropathy and without observed cases of febrile neutropenia.

Results of the study are presented at the 17th International Conference on Malignant Lymphoma (ICML)**, held June 13 – 17, 2023 in the Palazzo dei Congress, Lugano, Switzerland.

Incidence of classical Hodgkin lymphoma
Lymphoma is a general term for a group of cancers that originate in the lymphatic system affecting a type of white blood cell called lymphocytes. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Hodgkin lymphoma is distinguished by the presence of Reed-Sternberg cells that usually have a protein called CD30 on their surface.

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Approximately 8,830 cases of classical Hodgkin lymphoma will be diagnosed in the United States during 2023 and 900 people will die from the disease.[1] According to the International Agency for Research on Cancer in 2020, over 83,000 people worldwide were diagnosed with Hodgkin lymphoma and approximately 23,000 people died from this cancer.[2]

Standard of Care
Brentuximab vedotin + AVD chemotherapy (Adriamycin, vinblastine, dacarbazine) is a U.S. standard of care in advanced-stage classical Hodgkin lymphoma based on national treatment guidelines and is the only targeted therapy inclusive regimen that has a proven statistically significant overall survival benefit at 6-years of follow-up, reducing risk of death by 41% for these patients. [3][4]

“With teens and young adults primarily impacted by Hodgkin lymphoma, our goal is to develop curative treatments that improve survival while also reducing toxicity,” said Jeremy Abramson, MD, Director, Jon and Jo Ann Hagler Center for Lymphoma at Massachusetts General Hospital and principal investigator of the trial.

“The targeted agents of brentuximab vedotin and nivolumab have distinct mechanisms of action and demonstrated promising activity and safety in this early study; the omission of bleomycin and vinblastine chemotherapy likely contributed to the absence of certain adverse events.”

“We are encouraged by the promising clinical outcomes of an brentuximab vedotin plus nivolumab combination with reduced chemotherapy as we seek to maximize efficacy and improve tolerability in both early- and late-stage classical Hodgkin lymphoma,” said Roger Dansey, President of Research and Development and Chief Medical Officer at Seagen.

Study design
The SGN35-027 study is an ongoing open-label, multiple part, multicenter, phase 2 clinical trial evaluating two different brentuximab vedotin treatment combinations in patients with advanced and early-stage cHL. The trial includes three parts (Parts A, B, and C).

Part A is evaluating the combination of brentuximab vedotin and doxorubicin, vinblastine, and dacarbazine (A+AVD) with primary granulocyte-colony stimulating factor (G-CSF) prophylaxis, while Parts B and C are evaluating brentuximab vedotin in combination with nivolumab, doxorubicin, and dacarbazine (AN+AD) as a first-line treatment in advanced and early-stage disease, respectively.

Part B is evaluating the combination in patients with Ann Arbor stage II bulky (mediastinal mass 10 cm), stage III or IV cHL.

Part C is evaluating the combination in patients with stage I or II cHL without bulky mediastinal disease (<10 cm). The participating patients received 4 cycles of brentuximab vedotin 1.2 mg/kg, nivolumab 240 mg, doxorubicin 25 mg/m2, and dacarbazine 375 mg/m2. The primary endpoint for Part A is the proportion of patients with treatment-emergent febrile neutropenia.

The primary endpoint for Parts B and C is the proportion of participants with complete response at end of treatment according to the Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC). Incidence of adverse events is a secondary endpoint for Parts B and C.

Study outcomes
Of 154 patients with early-stage disease in Part C of the study, 150 were included at the time of efficacy assessment.  The results showed:

  • A 98% ORR (95% CI: 94.3, 99.6) and a 93% CR rate (95% CI: 87.3, 96.3) at end of treatment (EOT).
  • Follow-up is ongoing and progression-free survival (PFS) results are not yet available.
  • The most frequently reported treatment-related treatment-emergent adverse events (TRAEs) of any grade occurring in more than 30 percent of patients were nausea (65%), peripheral sensory neuropathy (47%) and fatigue (44%).
  • Peripheral sensory neuropathy was primarily low grade (3% Grade ≥3).
  • There were no cases of febrile neutropenia.
  • Immune-mediated AEs observed to date are consistent with the individual safety profile of nivolumab.
  • There were no grade 5 adverse events.

Updated data results from Part B of the study in patients with advanced-stage disease (n=57) were presented at the European Hematology Association (EHA) 2023 Congress in Frankfurt, Germany June 8-11, which showed an estimated 95% 12-month PFS rate and 93% 18-month PFS rate, an ORR of 95% and CR rate of 89% at EOT. The most frequently reported TRAEs of any grade occurring in more than 30 percent of patients were nausea (65%), fatigue (49%), peripheral sensory neuropathy (44%) and alopecia (35%).

Late breaking news
Also, to be presented in a late-breaking session, are three-year results from a 1,500-patient phase 3 trial from the German Hodgkin Study Group (HD21; ClinicalTrials.gov identifier: NCT02661503) evaluating non-inferiority efficacy and potential for reduced toxicity of an brentuximab vedotin regimen (BrECADD) compared to the highly efficacious yet chemotherapy intensive escalated BEACOPP regimen, commonly used outside of the U.S.

The findings from this separate study show that a brentuximab vedotin-containing regimen was not only non-inferior to one of the most highly effective yet chemotherapy-intense regimen commonly used in Europe, the brentuximab vedotin combination had superior progression-free survival and reduced toxicity. The results confirmed that patients receiving  the brentuximab vedotin-containing regimen called BrECADD (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) had a better Progression Free Survival (PFS) at 3 years with reduced toxicity than patients in control arm who received the escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone), known as eBEACOPP, regimen. In this study, the 3-year PFS was 92.3% for escalated BEACOPP and 94.9% for BrECADD with a HR of 0.63 (99% CI 0.37–1.07) – a 37% reduction in risk of disease progression.

The study results from the HD21 will be presented in a late-breaking presentation on Saturday June 17 on June 17, 2023.

Note:* Brentuximab vedotin is an antibody-drug conjugate (ADC) comprised of a CD30-directed monoclonal antibody attached by a protease-cleavable linker to a microtubule disrupting agent, monomethyl auristatin E (MMAE), utilizing Seagen’s proprietary technology. The ADC employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-positive tumor cells. Brentuximab vedotin is approved for seven indications in the U.S. and five indications in Europe, where Takeda has commercialization rights.

** The 17th International Conference on Malignant Lymphoma (ICML) is organized by the Foundation for the Institute of Oncology Research (IOR) in cooperation with the American Association for Cancer Research (AACR), the European School of Oncology (ESO) and the European Society for Medical Oncology (ESMO).

Clinical trials
Clinical Trial of Brentuximab Vedotin in Classical Hodgkin Lymphoma (SGN35-027) – NCT03646123
HD21 for Advanced Stages – NCT02661503

Highlights of Prescribing Information
Brentuximab vedotin (Adcetris®; Seagen/Takeda)[Prescribing Information]
Nivolumab (Opdivo®; Bristol-Myers Squibb)[Prescribing Information]
Doxorubicin (Adriamycin®)[Prescribing Information]
Dacarbazine (DTIC-Dome®/Imidazole)[Prescribing Information]

References
[1] Key Statistics for Hodgkin Lymphoma. American Cancer Society. Online. Last accessed on June 13, 2023
[2] Hodgkin Lymphoma. International Agency for Research on Cancer / WHO / Globocan 2020. Online. Last accessed on June 13, 2023
[3] Hodgkin Lymphoma. NCCN Guidelines (Version 2.2023). Online. Last accessed on June 13, 2023
[4] Ansell SM, Radford J, Connors JM, Długosz-Danecka M, Kim WS, Gallamini A, Ramchandren R, Friedberg JW, Advani R, Hutchings M, Evens AM, Smolewski P, Savage KJ, Bartlett NL, Eom HS, Abramson JS, Dong C, Campana F, Fenton K, Puhlmann M, Straus DJ; ECHELON-1 Study Group. Overall Survival with Brentuximab Vedotin in Stage III or IV Hodgkin’s Lymphoma. N Engl J Med. 2022 Jul 28;387(4):310-320. doi: 10.1056/NEJMoa2206125. Epub 2022 Jul 13. PMID: 35830649.
[5] Borchmann P, Moccia AA, Greil R, Schneider G, Hertzberg M, Schaub V, Hüttmann A, Keil F, Dierlamm J, Hänel M, Novak U, Meissner J, Zimmermann A, Mathas S, et al. BrECADD is Non-inferior to eBEACOPP in Patients with Advanced Stage Classical Hodgkin Lymphoma: Efficacy Results of the GHSG Phase III HD21 Trial. Volume 41, Issue S2
Supplement: 17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 ‐ 17 June, 2023. Pages 881-882. First published: 09 June 2023. [Article]

Featured image courtesy TCR Project on Unsplash. Used with permission.

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