ASH 2016 | Brentuximab vedotin plus RCHP appears an effective and well tolerated frontline therapy in high-intermediate/high-risk DLBLC expressing CD30

On 3–6 December 2016 in San Diego, CA, the 58th Annual Meeting & Exposition of the American Society of Hematology (ASH) took place.

On Saturday 3rd December, an oral abstract session was held between 9:30am and 11:00am in the “Aggressive Lymphoma (DLBCL and Other Aggressive B-Cell NHLs) – Results from Retrospective/Observational Studies Program” category. This session was moderated by Oreofe Odejide, MD, MPH, of the Dana-Farber Cancer Institute, and Carla Casulo, MD, of the University of Rochester Medical Center.

Abstract #104 was presented during this session, titled “Results of an Ongoing Phase 2 Study of Brentuximab Vedotin with Rchp As Frontline Therapy in Patients with High-Intermediate/High-Risk Diffuse Large B Cell Lymphoma (DLBCL)” by Lihua E. Budde, MD, PhD, of the Hematology & Hematopoietic Cell Transplantation department, City of Hope National Medical Center, Duarte, CA, and colleagues.

This ongoing study is split into parts. Part 1 included patients with high-intermediate or high-risk DLBCL who were administered 1.2 or 1.8mg/kg brentuximab vedotin plus RCHOP. However, 3 of the initial 10 patients treated at the 1.8mg/kg dose level developed grade 3 peripheral neuropathy and so all further patients enrolled received treatment at the lower dose of 1.2mg/kg brentuximab vedotin plus RCHOP. After enrollment was completed for Part 1, a protocol amendment took place for a non-randomized portion of the study (Part 2; NCT01925612) aimed at determining the efficacy and safety of 6 cycles 1.8mg/kg brentuximab vedotin plus RCHP. Part 3 is an open-labelled, randomized study comparing brentuximab vedotin + RCHP to RCHOP. This presentation included initial results from Part 2 and updated results from Part 1. 

Part 2 

• At time of analysis, 11 patients were treated (7 males, 4 female, 22–78 years of age) 
• ORR = 91% (9 CRs, 1 PR); progressive disease occurred in one patient after Cycle 4 
• The most common (>20%) treatment-emergent AEs were alopecia (73%), nausea (73%), fatigue (64%), constipation (55%), peripheral sensory neuropathy (55%), neutropenia (36%), throat irritation (36%), chills (27%), diarrhea (27%), headache (27%), and stomatitis (27%) 
• Serious AEs occurred in 5 patients and included febrile neutropenia, bacteremia, nausea, pneumocystis jiroveci pneumonia, pulmonary embolism, and vomiting 
• Peripheral sensory neuropathy occurred in 6 patients; all grade 1 or 2 

Part 1 

• 18-month PFS in patients with CD30 expression (n=25) or without detectable CD30 expression (n=24) by IHC was 79% (95% CI: 57%, 91%) versus 58% (95% CI: 36%, 75%), respectively 
• OS in CD30 detectable versus CD30 undetectable was 92% (95% CI: 71%, 98%) versus 67% (95% CI: 44%, 82%), respectively 
• Treatment-emergent peripheral neuropathy was reported in 38/51 patients (75%) who were administered brentuximab vedotin plus RCHOP 
• Resolution of all or some of the peripheral neuropathy occurred in 21/38 patients (55%) 

It was concluded that 1.8mg/kg brentuximab vedotin plus RCHP is an effective frontline therapy in high-intermediate/high-risk DLBCL expressing CD30 and appears well tolerated.  

Abstract 

Introduction: DLBCL is the most common lymphoid neoplasm in adults (Swerdlow 2016). While durable CRs are achieved in approximately 70% of patients (pts) with frontline RCHOP therapy (Pfreundschuh 2008), pts with high-risk features often experience disease resistance or relapse. In Part 1 of an ongoing study, pts with high-intermediate or high risk DLBCL by international prognostic index (IPI) scores, regardless of CD30 expression by IHC, were treated with 1.2 or 1.8 mg/kg brentuximab vedotin (BV) combined with RCHOP. After 3 of the first 10 pts treated at 1.8 mg/kg BV+RCHOP developed Grade 3 peripheral neuropathy (per Standardized MedDRA Query [SMQ]), all pts enrolled subsequently received treatment with 1.2 mg/kg BV+RCHOP. Following completion of enrollment in Part 1, the protocol was amended to enroll a non-randomized portion of the study (Part 2) evaluating the safety and efficacy of 1.8 mg/kg BV+RCHP (Yasenchak 2015), followed by an open-label, randomized portion comparing BV+RCHP to RCHOP (Part 3). Initial results from Part 2 and updated results from Part 1 are reported here. 

Methods: For Part 2 of the study, pts with CD30-expressing high-intermediate and high-risk DLBCL were treated with up to 6 cycles of 1.8 mg/kg BV+RCHP (NCT01925612). Key inclusion criteria were CD30 expression by IHC performed by a local pathology lab and standard IPI scores of 3–5 or age-adjusted IPI (aaIPI) scores of 2–3 (high-intermediate/high risk). CD30 expression was confirmed by a central pathology lab, although CD30 expression by local pathology lab was required for eligibility. Disease response was evaluated with PET/CT per Cheson 2007. 

Results: At the time of analysis for this ongoing study, 11 pts in Part 2 were treated with BV+RCHP (7 male, 4 female; 22‑78 yrs). Of these pts, 9 had high-intermediate risk (IPI 3, aaIPI 2) and 2 had high risk disease (IPI 4-5, aaIPI 3), 6 had Stage IV disease, and 6 had an ECOG score of 2. At the end of treatment, the overall response rate was 91% (9 CR, 1 PR); 1 pt had PD after Cycle 4. The most frequent (>20%) treatment-emergent adverse events (AEs) were alopecia and nausea (73% each); fatigue (64%); constipation and peripheral sensory neuropathy (55% each); neutropenia and throat irritation (36% each); and chills, diarrhea, headache, and stomatitis (27% each). Grade 3 or 4 AEs occurred in 8 pts and 5 pts had serious AEs, which included febrile neutropenia, bacteremia, nausea, pneumocystis jiroveci pneumonia, pulmonary embolism, and vomiting. Peripheral sensory neuropathy occurred in 6 pts and all were Grade 1 or 2 events; no peripheral motor neuropathy AEs were reported. No AEs were fatal or led to discontinuation. One pt discontinued treatment after Cycle 4 due to disease progression. 

For the first 51 pts in Part 1, the progression-free survival (PFS) at 18 months for pts with CD30 expression (25 pts) or without detectable CD30 expression (24 pts) by IHC was 79% (95% CI: 57%, 91%) versus 58% (95% CI: 36%, 75%), respectively. Overall survival for pts was 92% (95% CI: 71%, 98%) versus 71% (95% CI: 48%, 85%), respectively. Ten pts had pre-existing peripheral neuropathy (per SMQ) at study entry. Treatment-emergent peripheral neuropathy (per SMQ) was observed in 75% of pts (38/51) who received BV+RCHOP; 55% of these pts (21/38) had resolution of all or some peripheral neuropathy events. 

Conclusions: 1.8 mg/kg BV+RCHP is active as frontline treatment in CD30-expressing, high-intermediate/high risk DLBCL. When combined with RCHP, 1.8 mg/kg BV appears to be well-tolerated. The PFS and OS for pts with CD30-expression who received BV+RCHOP appear promising. The study is currently ongoing in pts with CD30-expressing high-intermediate/high risk DLBCL to assess the safety and activity of 1.8 mg/kg BV+RCHP versus standard RCHOP.