“I was taught that the way of progress was neither swift nor easy.”
—Marie Curie
To complement The ASCO Post’s continued comprehensive coverage of the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition, here are two abstracts selected from the meeting proceedings focusing on the use of the CD30-directed antibody-drug conjugate brentuximab vedotin in challenging clinical scenarios. For full details of these study abstracts, visit ashpublications.org.
Syed Ali Abutalib, MD
Julie M. Vose, MD, MBA, FASCO
Older Patients With or Without Comorbid Conditions
ABSTRACT 471: Phase II SGN35-015 study of front-line brentuximab vedotin as monotherapy or in combination for older adults (≥ 60 years) newly diagnosed with classic Hodgkin lymphoma (ClinicalTrials.gov identifier NCT01716806)1
Background: In general, older adults with classic Hodgkin lymphoma have poor outcomes relative to younger patients, often due to comorbidities and toxicities related to standard first-line chemotherapy. Brentuximab vedotin has exceptional clinical activity in patients with relapsed and refractory classic Hodgkin lymphoma.2
Methods: Patients in Part A received brentuximab vedotin monotherapy on day 1 of every 3-week cycle (n = 26); patients in Part B received brentuximab vedotin plus dacarbazine (375 mg/m2); those in Part C were given brentuximab vedotin plus bendamustine (70 mg/m2); and patients in Part D received brentuximab vedotin plus nivolumab (3 mg/kg). The median ages of the patients were 78, 69, 75, and 72 in Parts A, B, C, and D, respectively, and 62% of patients (range, 45%–70%) reported impaired physical functioning at baseline. Most patients had stage III or IV disease.
Results
- A: Brentuximab vedotin monotherapy (n = 26); B: Brentuximab vedotin plus dacarbazine (n = 19); C: Brentuximab vedotin plus bendamustine (n = 20); D: Brentuximab vedotin plus nivolumab (n = 20).
- Median progression-free survival in the efficacy evaluable set was A: 10.5 months (confidence interval [CI] = 5.6–7.5 months), B: 46.8 months (CI = 11.0–68.7 months), C: 40.3 months (CI = 4.8 months to not reported), and D: not reached (CI = 9.4 months to not reported), respectively.
- Median overall survival in the full-analysis set was A: 77.5 months (CI = 40.1 months to not reported), B: 64.0 months (CI = 53.4 months to not reached), C: 46.9 months (CI = 6.8 months to not reached), and D: not reached (CI = not reached to not reached), respectively.
- Treatment-related adverse events ≥ grade 3 occurred in A: 50%, B: 37%, C: 70%, and D: 60%, respectively; peripheral neuropathy was most common (A: 35%, B: 26%, C: 20%, and D: 35%, respectively).
- Treatment-related serious adverse events occurred in A: 12%, B: 11%, C: 40%, and D: 5%, respectively.
- Treatment discontinuation due to related adverse events occurred in A: 42%, B: 42%, C: 40%, and D: 30% of patients; it was most commonly due to neuropathy (A: 38%, B: 37%, C: 30%, and D: 20%, respectively).
- Part C enrollment (brentuximab vedotin plus bendamustine) closed early due to multiple acute toxicities.
Clinical Implications: Older adults with classic Hodgkin lymphoma and multiple comorbidities have very high response rates and a clinically meaningful improvement in progression-free survival with brentuximab vedotin as monotherapy or combined with other single agents and improved tolerability vs combination chemotherapy. The median overall survival exceeded 6 years with brentuximab vedotin monotherapy. Brentuximab vedotin plus nivolumab or dacarbazine appeared to be the most reasonable combination treatment options in this study of older adults newly diagnosed with classic Hodgkin lymphoma.
Prevention of Relapse After Autologous Transplant
ABSTRACT 472: Multicenter phase II study of consolidation with brentuximab vedotin and nivolumab after autologous hematopoietic cell transplantation (auto-HCT) in patients with relapsed and refractory (modified) high-risk classic Hodgkin lymphoma3
Background: Historically, these patients have poor outcomes, including a median survival of 2.4 years from auto-HCT and 1.2 years from auto-HCT if relapse occurs less than 1 year from auto-HCT. The phase III AETHERA study demonstrated that after auto-HCT, consolidation with brentuximab vedotin (16 cycles = 12 months) in these high-risk patients improved progression-free survival compared with placebo, particularly in individuals who had at least two risk factors.4 The study-defined high-risk factors included the following: 1) a history of refractory classic Hodgkin lymphoma; 2) relapsed or progressive classic Hodgkin lymphoma that occurred less than 12 months from the end of front-line therapy; and 3) extranodal involvement at the time of pre–auto-HCT relapse. Brentuximab vedotin–exposed patients with classic Hodgkin lymphoma were excluded from AETHERA; however, in clinical practice, brentuximab vedotin is increasingly used prior to auto-HCT. The PD-1 receptor blocker nivolumab has shown clinical activity, as a single agent and in combination with nivolumab, in patients with relapsed and refractory classic Hodgkin lymphoma.5,6
Methods: After HCT, adult patients with high-risk Hodgkin lymphoma defined as having at least one of the following modified AETHERA risk factors were eligible: primary refractory classic Hodgkin lymphoma; relapse within less than 1 year of completing initial treatment; extranodal disease at relapse; B symptoms at relapse, requiring at least one salvage treatment; and not in complete remission at the time of auto-HCT. In all, 21 patients (36%) had one modified AETHERA risk factor, 23 (40%) had two, and 14 (24%) had three. The median follow-up from study treatment initiation was 15.7 months (range, 2.8–35.5 months). Prior use of brentuximab vedotin or a PD-1 receptor blocker was allowed if patients were not refractory. Starting between 30 and 75 days after auto-HCT, patients received 1.8 mg/kg of brentuximab vedotin and 3 mg/kg of nivolumab every 21 days for a planned eight cycles. If one drug was discontinued due to toxicity, the other could be continued. The primary endpoint was 18-month progression-free survival from study treatment initiation.
Results
- Of 56 patients, 29 patients (49%) completed the planned eight cycles, and 45 patients (76%) completed eight cycles of one drug. Brentuximab vedotin was discontinued in eight patients, and nivolumab was discontinued in seven patients. The dose of brentuximab vedotin was reduced to 1.2 mg/kg in 11 patients.
- The most common adverse events related to brentuximab vedotin and nivolumab were peripheral neuropathy, neutropenia, fatigue, diarrhea, nausea, arthralgia, and aspartate transferase elevation.
- The most frequent grade 3 or 4 adverse events were neutropenia (31%), pneumonitis (7%), and alanine transferase elevation (5%). Immune-related adverse events requiring systemic corticosteroids occurred in 18 patients (31%).
- Of the 45 patients who completed eight cycles of treatment, 6 patients were converted to complete remission with combination therapy. There were two progression-free survival events, one relapse at 15 months, and one Pneumocystis jirovecii pneumonia–related death after prophylaxis.
- The estimated 18-month progression-free survival and overall survival in all patients were 95% and 98%, respectively.
Clinical Implications: Therapy with two agents, brentuximab vedotin and nivolumab after auto-HCT, appears to be a promising approach to prevent relapse in relapsed and refractory high-risk classic Hodgkin lymphoma. However, the planned eight cycles were successfully completed in 49% of patients. Peripheral neuropathy and neutropenia were common and remain a concern. Nivolumab plus brentuximab vedotin was generally tolerable, although immune-related adverse events were observed more frequently compared with when these drugs are given in the pretransplant setting.
Dr. Abutalib is Associate Director of the Hematology and BMT/Cellular Therapy Programs and Director of the Clinical Apheresis Program at the Cancer Treatment Centers of America, Zion, Illinois; Associate Professor at Rosalind Franklin University of Medicine and Science; and Founder of the journal Advances in Cell and Gene Therapy. Dr. Vose is the Neumann M. and Mildred E. Harris Professor and Chief of the Division of Oncology/Hematology at the Buffett Cancer Center, University of Nebraska Medical Center, Omaha.
DISCLOSURE: Dr. Abutalib has served on the advisory board for AstraZeneca. Dr. Vose has received research support from AstraZeneca, BMS, Incyte, Kite Pharma, Novartis, Seattle Genetics, Loxo, and Epizyme and has received honoraria for consulting from AbbVie, Vaniam Group, Janssen/Pharmacyclics, Kite Pharma, AstraZeneca, Verastem, Miltenyi, Loxo, Allogene, Celgene, Roche, Genentech, Karyopharm, and MorphoSys.
REFERENCES
1. Yasenchak CA, Bordoni R, Patel-Donnelly D, et al: Frontline brentuximab vedotin as monotherapy or in combination for older Hodgkin lymphoma patients. 2020 ASH Annual Meeting & Exposition. Abstract 471. Presented December 6, 2020.
2. Chen R, Gopal AK, Smith SE, et al: Five-year survival and durability results of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma. Blood 128:1562-1566, 2016.
3. Herrera AF, Chen L, Nieto Y, et al: Consolidation with nivolumab and brentuximab vedotin after autologous hematopoietic cell transplantation in patients with high-risk Hodgkin lymphoma. 2020 ASH Annual Meeting & Exposition. Abstract 472. Presented December 6, 2020.
4. Moskowitz CH, Walewski J, Nademanee A, et al: Five-year PFS from the AETHERA trial of brentuximab vedotin for Hodgkin lymphoma at high risk of progression or relapse. Blood 132:2639-2642, 2018.
5. Armand P, Engert A, Younes A, et al: Nivolumab for relapsed/refractory classic Hodgkin lymphoma after failure of autologous hematopoietic tell Transplantation: Extended follow-up of the multicohort single-arm phase II CheckMate 205 trial. J Clin Oncol 36:1428-1439, 2018.
6. Herrera AF, Moskowitz AJ, Bartlett NL, et al: Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma. Blood 131:1183-1194, 2018.
