Brentuximab Vedotin Monotherapy and in Combination with Dacarbazine in Frontline Treatment of Hodgkin Lymphoma in Patients Aged 60 Years and Above: Interim Results of a Phase 2 Study

Introduction

Patients (pts) aged ≥60 yrs with Hodgkin lymphoma (HL) have significantly inferior outcomes compared to younger pts due to factors including comorbidities, poorer performance status, advanced stage disease, and adverse biologic features (Evens 2008). Although standard frontline ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) is curative for most pts, those aged ≥60 yrs commonly experience an increased incidence of regimen-related toxicity leading to suboptimal dosing and higher rates of relapse. New treatment options with better tolerability and improved efficacy are needed.

Brentuximab vedotin (ADCETRIS^®), an anti-CD30 antibody-drug conjugate, has a manageable safety profile and durable activity as a single-agent in relapsed HL. Brentuximab vedotin + dacarbazine had durable activity in preclinical tumor models (McEarchern 2010), and frontline brentuximab vedotin + AVD showed robust antitumor activity (96% complete remission [CR] rate) and manageable toxicity (Younes 2013). Because single-agent brentuximab vedotin demonstrates efficacy and safety in HL, and dacarbazine is a critical component of the ABVD regimen (Borchmann 2010) with demonstrated durability and tolerability, this phase 2, open-label, frontline study of brentuximab vedotin in HL pts aged ≥60 yrs was amended to evaluate efficacy and durability of response of brentuximab vedotin + dacarbazine (NCT01716806) in a setting of a high response rate and tolerability with monotherapy.

Methods

About 50 treatment-naïve pts aged ≥60 yrs with HL (30 monotherapy; 20 combination therapy) are to be enrolled. Eligible pts have ECOG ≤3 and are ineligible for or have declined conventional combination chemotherapy. For monotherapy, brentuximab vedotin 1.8 mg/kg is administered every 3 weeks for up to 16 or more cycles in pts achieving stable disease (SD) or better. For combination therapy, dacarbazine 375 mg/m²is given for Cycles 1–12, followed by monotherapy for Cycles 13–16. Pts with unacceptable toxicity to dacarbazine prior to completion of 12 cycles may receive monotherapy for a total of 16 cycles or more. Response assessments occur after Cycles 2, 4, 8, 12, 16 and every 6 cycles thereafter. The primary endpoint is objective response rate (ORR) per the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Key secondary endpoints include CR rate, progression-free survival (PFS), and safety.

Results

Thirty-three evaluable pts have enrolled thus far (n=27 monotherapy; n=6 combination). Median age for all pts was 77 yrs (range, 64–92), 58% were male, and 27% had ECOG 2–3. Most had stage III–IV disease (70%) and 48% had moderate age-related renal insufficiency at baseline (creatinine clearance 30–60 mL/min). Three pts had below normal (range, 40–50%) and 8 pts had borderline (range, 55–56%) cardiac ejection fraction at baseline. Pts have received a median of 7 cycles of monotherapy (range, 3–18) or 4 cycles of combination therapy (range, 1–7). Seven pts remain on monotherapy treatment, while 9 discontinued for progressive disease after achieving a CR or PR and 1 after SD, 7 for adverse events (AEs) (6 due to Grade 2 or 3 peripheral sensory or motor neuropathy; 1 due to a serious adverse event [SAE] of Grade 3 orthostatic hypotension), 2 for pt decision, and 1 for other, non-AE. All pts on combination therapy are still on treatment.

The ORR for monotherapy was 93% (n=25) with a median PFS of 8.7 months to date (range, 2.6+ to 13.4+). The CR rate was 70% (n=19) and median PFS for pts with CR was also 8.7 months (range, 2.9+ to 13.4+). All 6 pts treated with combination therapy achieved an objective response (100% ORR; 2 CRs, 4 PRs) and median PFS has not been reached for these pts (range, 1.2+ to 2.8+ months).

With monotherapy, treatment-related AEs ≥ Grade 3 occurring in >1 pt included peripheral sensory neuropathy (22%), peripheral motor neuropathy, and rash (7% each). With the combination, 1 pt had an SAE of Grade 3 clostridium difficile colitis attributed to dacarbazine. No related Grade 4 AEs occurred; no pts died within 30 days of last dose.

Conclusions

In this planned interim analysis, compelling antitumor activity with high ORRs (93% monotherapy; 100% combination) and acceptable tolerability are demonstrated with both brentuximab vedotin alone and with dacarbazine in a historically challenging HL population. Further study of highly active regimens incorporating brentuximab vedotin for elderly HL is anticipated.