Clinically meaningful progression-free survival (PFS), a secondary endpoint, was observed in a ongoing Phase 2 study evaluating brentuximab vedotin (Adcetris®; Seagen/Takeda), an antibody-drug conjugate or ADC, in combination with the PD-1 inhibitor nivolumab (Opdivo®; Bristol-Myers Squibb) and standard chemotherapy agents doxorubicin (Adriamycin®; Pfizer) and dacarbazine (AN+AD) as first-line treatment for early and advanced stage classical Hodgkin lymphoma (cHL).

This is the first time 12-month PFS results were presented for the treatment combination, which avoids use of vinblastine and bleomycin in patients with early stage cHL.

The results from the trial, called SGN35-027 (NCT03646123), were presented in an oral session at the 65th American Society of Hematology Annual) Meeting & Exposition, held December 9 – 12, 2023 in San Diego, CA.

Proven foundation
Brentuximab vedotin, an ADC, is 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 drug is a proven foundation of care for CD30-expressing lymphomas with more than 120,000 patients treated globally across seven indications. In combination with Adriamycin, vinblastine and dacarbazine (AVD) chemotherapy, brentuximab vedotin is the first medicine to include overall survival data in its Prescribing Information for previously untreated Stage III/IV cHL.

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.

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  • Hodgkin lymphoma is distinguished by the presence of Reed-Sternberg cells that usually have a protein called CD30 on their surface. 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]

“Hodgkin lymphoma commonly strikes young adults, and our goal is to achieve the highest cure rate possible while reducing treatment and toxicity burden,” noted Jeremy Abramson, M.D., Director, Jon and Jo Ann Hagler Center for Lymphoma at Massachusetts General Hospital, and principal investigator of the part of the trial that evaluated patients with early stage cHL.

“These data show encouraging activity and safety for combining an ADC and immunotherapy, two medicines that have distinct and complementary mechanisms of action, allowing reduced reliance on traditional cytotoxic chemotherapies,” Abramson added.

“These data continue to demonstrate favorable clinical outcomes of an brentuximab vedotin plus nivolumab immunotherapy combination that reduces chemotherapy treatment burden and warrant further study,” said Roger Dansey, M.D., President, Research and Development and Chief Medical Officer at Seagen.

Study Results Part B
SGN35-027 (NCT03646123) Part B is investigated the novel brentuximab vedotin combination in 57 patients with advanced-stage cHL. This part of the study enrolled patients with stage II bulky mediastinal disease (≥10 cm), stage III, or stage IV cHL. Patients received up to 6 cycles of doxorubicin 25 mg/m2 + dacarbazine 375 mg/m2 (AN+AD) in combination with brentuximab vedotin 1.2 mg/kg and nivolumab 240 mg. The primary efficacy endpoint was complete response [CR] rate at end of therapy [EOT]. [3]

  • Among 56 efficacy-evaluable patients, 95% had an OR (95% CI: 85.1, 98.9) and 89% had a CR (95% CI: 78.1, 96.0).
  • 88% of patients who responded (95% CI: 75.7, 94.6) had a DOR beyond 24 months; 88% of patients who had a CR (95% CI: 76.0, 94.6) had a DOCR beyond 24 months.
  • The estimated PFS rate at 24 months was 88% (95% CI: 75.7, 94.6), with a median follow-up of 24.2 months (95% CI: 23.4, 26.9).
  • The most frequently reported TEAEs Grade 3 or higher were increased alanine aminotransferase (11%) and neutropenia (9%).
  • Peripheral sensory neuropathy was primarily low grade (4% Grade ≥3).
  • No febrile neutropenia and no deaths were reported.
  • IMAEs were primarily low-grade and consistent with the individual safety profile of nivolumab. No subsequent radiation therapy was given to patients.

Study results Part C
SGN35-027 Part C investigated the novel brentuximab vedotin combination in 154 patients with early stage (non-bulky Stage I or II) cHL. This part of the study enrolled patients with Ann Arbor stage I or II cHL without bulky disease, defined as those with a single node or nodal mass with a <10-cm diameter on computed tomography imaging. Participating patients received 4 cycles of doxorubicin 25 mg/m2 + dacarbazine 375 mg/m2  in combination with brentuximab vedotin 1.2 mg/kg and  nivolumab 240 mg  intravenously on days 1 and 15 of each 28-day cycle). Per protocol, G-CSF prophylaxis was not required for patients receiving this treatment regimen. The primary endpoint is complete response (CR) rate at end of treatment (EOT). Secondary endpoints include progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), and duration of complete response (DOCR), as well as safety and tolerability. [4]

  • Among 150 efficacy-evaluable patients, 98% had an overall response (OR) (95% CI: 94.3, 99.6) and 93% had a complete response (CR) (95% CI:88.1, 96.8) at the end of treatment.
  • 99% of patients who responded (95% CI: 95.0, 99.9) had a duration of response (DOR) beyond 12 months; 98% of patients who had a complete response (95% CI: 93.7, 99.6) had a duration of CR (DOCR) beyond 12 months.
  • The PFS rate was 100% (95% CI: 100, 100) at 12 months and 97% (95% CI: 90.3, 99.1) at 18 months.
  • The most frequently reported treatment-emergent adverse events (TEAEs) Grade 3 or higher were neutropenia (9%), increased alanine aminotransferase (7%), and increased aspartate aminotransferase (5%).
  • Peripheral sensory neuropathy was primarily low grade (3% Grade ≥3).
  • There were no cases of febrile neutropenia and no deaths.
  • Treatment-emergent immune-mediated adverse events (IMAEs) were primarily low-grade and consistent with the individual safety profile of nivolumab.

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Note: * SGN35-027 is an ongoing open-label, multiple part, multicenter, single-arm Phase 2 clinical trial evaluating brentuximab vedotin treatment combinations in patients with early- and advanced-stage cHL. Parts B and C of the trial are investigating brentuximab vedotin in combination with the PD-1 inhibitor nivolumab and chemotherapy agents doxorubicin and dacarbazine. Part B is evaluating the combination in patients with 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 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).

Clinical trial
Clinical Trial of Brentuximab Vedotin in Classical Hodgkin Lymphoma. ClinicalTrials.gov ID NCT03646123

Highlights of Prescribing Information
Brentuximab vedotin (Adcetris®; Seagen/Takeda)[Prescribing Information]
Nivolumab (Opdivo®; Bristol-Myers Squibb)[Prescribing Information]

References
[1] American Cancer Society. Key Statistics for Hodgkin Lymphoma. Online. Last accessed on November 30, 2023.
[2] International Agency for Research on Cancer. Hodgkin Lymphoma. Online. Last accessed on November 30, 2023.
[3] Lee HJ, Flinn IW, Melear J, Ramchandren R, Friedman J, Burke JM, Linhares Y, Gonzales PA, Raval M, Chintapatla R, Feldman T, Yimer HA, Islas-Ohlmayer M, Dean A, Rana V, Gandhi M, Renshaw JS, Ho L, Fanale MA, Guo W, and Yasenchak C. Oral #608: Brentuximab vedotin, nivolumab, doxorubicin, and dacarbazine for advanced stage classical Hodgkin lymphoma: Updated efficacy and safety results from the single arm Phase 2 study (SGN35-027 Part B) [Abstract]
[4] Abramson JS, Straus DJ, Bartlett NL, Burke JM, Lynch RC, Domenech ED, Hess B, Schuster SR, Linhares Y, Ramchandren R, Gandhi M, Mowat R, Shah H, Jurczak W,  Re A, Hahn U, Prince HM, Guo W, Ho L, Beck RC, Yasenchak CA, and Lee HJ. Oral #611: Brentuximab vedotin, nivolumab, doxorubicin, and dacarbazine (AN+AD) for early-stage classical Hodgkin lymphoma: Updated results reporting progression-free survival in an ongoing Phase 2 study (SGN35-027 Part C) [Abstract]

Featured image: General Views at the American Society of Hematology 64th Annual Meeting 2022. Photo Courtesy: 2022 © ASH/Matt Herp. Used with permission.

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