Brentuximab Vedotin Shows Encouraging Responses Rates, Tolerability in Older Patients With Hodgkin Lymphoma

The antibody-drug conjugate brentuximab vedotin (Adcetris) demonstrated high response rates with durability, as well as a tolerable safety profile among older patients with comorbid classical Hodgkin lymphoma (cHL), according to findings from the phase 2 SGN35-015 study (NCT01716806), which were presented virtually during the 2020 ASH Annual Meeting & Exposition.

Patients who are 60 years of age or older represent about 20% of the cHL population, yet these patients have inferior outcomes in comparison to their younger counterparts. The prognostic profile of these older patients with cHL includes variances in disease and biology, higher rates of advanced disease at the time of presentation, more comorbidities at baseline, and increased morbidity and mortality as a result of treatment.

The decision to utilize brentuximab vedotin in older patients with comorbid cHL was based on previously published 5-year data showing an 93% overall response rate (ORR) with the agent along with an 80% complete response (CR) rate in patients with relapsed or refractory cHL with good tolerability, explained Christopher A. Yasenchak, MD, during the ASH presentation. The agent also demonstrated a high ORR of 95% with CRs in 93% of patients when administered in combination with doxorubicin, vinblastine, and dacarbazine, followed by consolidation therapy with brentuximab vedotin. It was hypothesized that the drug may be an option for elderly patients as well as those who are considered to be frail.

Investigation of the potential of brentuximab vedotin in this patient population was executed in a 4-part study conducted in the front-line setting. The drug was administered at 1.8 mg/kg every 3 weeks for up to 16 cycles. There were 26 patients included in part A who received brentuximab vedotin monotherapy. The 20 patients in part B were given brentuximab vedotin in combination with dacarbazine at 375 mg/m². Part C also included 20 patients who were administered brentuximab vedotin plus bendamustine at 70 mg/m². Finally, 21 patients in part D received brentuximab vedotin in combination with 3 mg/kg of nivolumab (Opdivo).

A total of 80 patients were evaluable for efficacy including 25 from part A, 19 from part B, 17 from part C, and 19 from part D. Patients who received brentuximab vedotin alone in part A achieved a 92% ORR with CR in 72%, partial responses (PRs) in 20%, and stable disease (SD) in 8%. The median duration of response (DOR) for this cohort was 9.1 months (range, 2.8-81.4+). Subjects treated with brentuximab vedotin plus dacarbazine in part B had an ORR of 100% with CRs in 68%, and PRs in 32%. The cohort had a median DOR of 45.4 months (range, 0.0+ to 67.3). In part C, the combination of brentuximab vedotin and bendamustine led to an ORR of 100% with CRs in 88% of the patients and PRs in 12%. The median DOR for cohort C was 39.0 months (range, 0.0+ to 56.8+). Finally, the brentuximab plus nivolumab cohort achieved an ORR of 95% with a 79% CR rate and PRs in 16% and SD in 5%. The median DOR was not reached (NR) in part D (range, 1.4+ to 27.5+).

Progression-free survival (PFS) and overall survival (OS) were assessed for all patients enrolled. At a median follow-up of 54.5 months (range, 4.6-89.5) patients in part A had a median PFS of 10.48 months (95% CI, 5.55-77.47). The median OS for cohort A was 82 months (95% CI, 40.1-NR). Subjects in part B were followed for a median of 63.6 months (range, 6.7-77.0) and a

median PFS of 46.75 months (95% CI, 11-68.7) was observed. However, OS was NR in cohort B (95% CI, 53.4-NR).

At a median follow-up of 39.2 months (range, 0.4-66.0), patients in part C of the study had a median PFS of 40.34 months (95% CI, 4.01- NR). Patients in part C also achieved a median OS of 46.9 months (95% CI, 6.8-NR). Those in part D were followed for a median duration of 26.2 months (range, 0.5-41.7), and the median PFS was NR for this cohort (95% CI, 9.36-NR). The median OS among patients treated in part D was NR (95% CI, NR-NR).

Safety was assessed in the full set of patients as well. TEAEs of any kind occurred in 92% of patients treated in part A of the study, 100% of those in part B, 95% in part C, and 90% in part D. The emergence of TEAEs led to treatment discontinuation in 42%, 40%, 60%, and 38% of patients, respectively. The most common TEAE that led to treatment discontinuation in all parts of the study was peripheral neuropathy which occurred in 38% of patients in part A, 35% in part B, 30% in part C, and 29% in part D.

Grade 3 or higher TEAEs were observed in half of the part A cohort, 40% of part B, 80% of part C, and 62% of part D. Peripheral sensory neuropathy was the common grade 3 or higher TEAE observed. In addition, treatment-related serious TEAEs were observed included pyrexia, asthenia, febrile neutropenia, and hypotension. These events were observed in 12% of patients in part A, 15% in part B, 45% in part C, and 5% in part D.

Duration of treatment in the full analysis set was a median 25.6 weeks (range, 11-85) in part A, 33.9 weeks (range 6-82) in part B, 15.4 weeks (range 2-60) in part C, and 34.9 weeks (range, 2-56) in part D. The median number of brentuximab vedotin cycles was 8.0 (range, 3-23) for patients in part A, 10.5 (range, 2-27) in part B, 5.0 (range, 1-16) for those in part C, and 10.0 (range, 1-16) in part D.

Demographics and disease characteristics were assessed at baseline. The total population of the study include 87 patients. The median age was 74 years (range, 60-92) and the majority of patients were male (61%). Eighty percent of patients had an ECOG performance status of ≤ 1. The main histologic subtype of HL found in patients were nodular sclerosis (41%), mixed cellularity (22%), and the remaining 22% of patients had cHL not otherwise specified.

Seventy percent of patients in the study had stage III or IV disease, 41% had extra nodal involvement, and 40% had B symptoms. Patients who reported being “limited a lot” in more than 1 of their tasks made up 62% of the study population.

The findings from SGN35-015 warrant further research in elderly patients with cHL in addition to geriatric assessments.

Reference

Yasenchak CA, Bordon R, Patel-Donnelly D, et al. Frontline brentuximab vedotin as monotherapy or in combination for older hodgkin lymphoma patients. Presented at: 2020 ASH Annual Meeting; December 4-8, 2020; Virtual. Abstract 471.