Frontline Brentuximab Vedotin As Monotherapy or in Combination for Older Hodgkin Lymphoma Patients

Introduction: Older patients with classical Hodgkin lymphoma (cHL) have poor outcomes relative to younger patients, often due to comorbidities and toxicities related to standard first-line (1L) chemotherapy (5-yr PFS: 30%-45% vs 75%-80%) (Evens 2008; Proctor 2009). Brentuximab vedotin (BV), a CD30-directed antibody-drug conjugate, has robust activity in patients refractory to several lines of chemotherapy.

Methods: This phase 2, open-label study, SGN35-015 (NCT01716806), evaluated efficacy and tolerability of BV alone or combined with single-agents in treatment-naive cHL patients ≥60 yr. The full-analysis set (FAS) includes all patients who received BV (1.8 mg/kg IV). Patients in Part A received BV monotherapy on Day 1 of every 3-week cycle (n=26); Part B: BV+dacarbazine (DTIC; 375 mg/m²; n=19); Part C: BV+bendamustine (benda; 70 mg/m²; n=20); and Part D: BV+nivolumab (nivo; 3 mg/kg; n=20). The efficacy evaluable (EE) set includes FAS who had at least 1 post-baseline response assessment (n=25, 19, 17, 19).

Results: Demographic characteristics were generally similar: median age 78, 69, 75, and 72 yr in Parts A, B, C, and D, respectively, and 62% of patients (range 45%-70%) reported impaired physical functioning at baseline. Most patients had disease stage III/IV (62%, 68%, 75%, 80%), were ECOG 0/1 (77%, 74%, 80%, 95%), and male (54%, 68%, 50%, 75%). Median time from diagnosis was 1.2 to 1.5 mo (FAS; 10 Jan 2020 data cutoff). ORR were high (92% [95% CI: 74%, 99%], 100% [95% CI: 82.4%, 100%], 100% [95% CI: 80.5%, 100%], 95% [95% CI: 74%, 99.9%]) at a median follow-up of 59.4, 58.6, 51.3, and 19.4 mo in the EE data set. Median PFS in the EE set was 10.5 mo (95% CI: 5.6, 77.5) with monotherapy and 46.8 mo (95% CI: 11.0, 68.7), 40.3 mo (95% CI: 4.8, NR), and not reached (95% CI: 9.4, NR) in the combination parts. Median OS in the FAS set was 77.5 mo (95% CI: 40.1, NR) with monotherapy; 64.0 (95% CI: 53.4, NR), 46.9 (95% CI: 6.8, NR), and not reached (95% CI: NR, NR) in the combination parts. Treatment-related adverse event (AE) ≥ Grade 3 occurred in 50%, 37%, 70%, and 60% of patients; peripheral neuropathy (PN) was most common (35%, 26%, 20%, 35%). Treatment-related serious AEs occurred in 12%, 11%, 40%, and 5% of patients. Part C enrollment (BV+benda) closed early due to multiple acute toxicities. There were no treatment-related deaths in any part of the study. The median treatment cycles per patient were 8.0, 12.0, 5.0, and 14.5. Treatment discontinuation due to related AEs occurred in 42%, 42%, 40%, and 30% of patients, most commonly due to PN (38%, 37%, 30%, 20%).

Conclusions: Older patients with cHL and multiple comorbidities have very high response rates and a clinically meaningful improvement in PFS with BV as monotherapy or combined with other single agents and improved tolerability versus combination chemotherapy. Median overall survival exceeded 6 yrs with BV monotherapy. BV+nivo or BV+DTIC appeared to be the most reasonable combination treatment options in this study.