R2-CHOP in DLBCL: The E1412 and ROBUST Studies

Rachel Gerstein, PharmD
PGY2 Oncology Pharmacy Resident
Yale New Haven Hospital
New Haven, CT

The most common lymphoid malignancy among adults is diffuse large B-cell lymphoma (DLBCL). DLBCL accounts for approximately 30% of non-Hodgkin lymphomas (NHL).1 Stan­dard of care treatment for DLBCL is comprised of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone, also known as R-CHOP. The relapse rate after initial therapy is nearly 40% so the target of treatment has been refocused and is directed at the molecular structure of DLBCL.^1-3

As a heterogenous malignancy, DLBCL can be classified based on cell-of-origin (COO). The major classes of COO consist of ger­minal center B-cell-like (GCB), activated B-cell-like (ABC), and unclassified sub­types. These subtypes differ in terms of prognosis and response to treatment. ABC-DLBCL has been associated with a worse survival prognosis. Standard of care currently remains the same for all subtypes, but the addition of novel targeted agents to R-CHOP are being investigated to see if outcomes can be improved for ABC-DLBCL.^4-5 Preclinical studies suggested that the addition of lenalidomide provided a direct cytotoxic effect in patients with ABC-DLBCL.⁶

Lenalidomide is an analogue of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties.⁷ In a phase II study, lenalidomide in combination with R-CHOP (R2-CHOP) showed benefit in patients with DLBCL, especially in patients with non-GCB DLBCL.⁸ E1412 and ROBUST are two recently published trials that investigated the role of R2-CHOP in ABC-DLBCL.

US Intergroup Study ECOG-ACRIN E14129
E1412 was a prospective multicenter phase II signal-seeking study that compared R2-CHOP versus R-CHOP in newly diag­nosed untreated confirmed DLBCL patients who were at least 18 years of age with at least stage II bulky disease. Patients were excluded if they had known central nervous system (CNS) lymphoma, history of deep venous thrombosis or embolism, transformed lymphoma, or primary mediastinal large B-cell lymphoma.

Patients were randomized in a 1:1 fashion to receive R2- CHOP or R-CHOP for six cycles. All patients received R-CHOP21, which consisted of one dose each of rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 all on day 1, and prednisone 100 mg/m2 once a day on days 1-5 of each cycle every 21 days for 6 cycles. In the R2-CHOP arm, patients received lenalidomide 25 mg daily days 1-10 of each cycle in addition to the R-CHOP21; the R2-CHOP arm also received pegfilgrastim prophylaxis, while use in the R-CHOP21 was left to provider discretion.

The primary endpoint was progression-free survival (PFS) in all patients with a co-primary end point of PFS in ABC-DLBCL. The secondary endpoints were overall response rate (ORR), complete response (CR) rate, and overall survival (OS).

There were 349 patients enrolled into the study between August 2013 and January 2017. For the efficacy analysis, 280 patients were included: 145 for R2-CHOP and 135 for R-CHOP arm. Of 234 patients with evaluable COO, 122 had GCB-DLBCL and 94 had ABC-DLBCL. The median age was 66 years. Ninety-six percent of patients had stage III or IV disease, 46% had 2 or more extra-nodal sites of involvement, and 24% had International Prognos­tic Index (IPI) score of 4 or 5; these high-risk features were evenly balanced between arms. The median time from diagnosis to treatment was 21 days. The median follow-up time was 3.0 years.

The results showed R2-CHOP was associated with 34% reduction in risk of progression or death compared with R-CHOP (hazard ratio [HR], 0.66; one-sided P=0.03). The one-year PFS was 84% for R2-CHOP compared to 73% for R-CHOP. R2-CHOP superiority was consistent at the two- and three-year PFS analyses. R2-CHOP had a greater ORR (97% vs 92%; P=0.06) and CR (73% vs 68%, P=0.43) compared to R-CHOP. The 3-year OS was superior in the R2-CHOP group (83% vs 75%; one-sided P=0.05). Based on COO, improved PFS was seen with R2-CHOP over R-CHOP in patients with ABC (HR, 0.64; one-sided P=0.1). Key subgroup analysis of PFS showed a trend favoring R2-CHOP in patients younger than 60 years old, with IPI scores of 2-3.

The safety analysis included 337 treated patients, with 166 for R2-CHOP and 171 for R-CHOP. There were six intended treatment cycles and 86% of R2-CHOP patients and 85% of R-CHOP patients completed all six cycles. The grade 3 or higher adverse events (AE) that significantly differed between the treatment groups were diarrhea (6% v 1%, P=0.005), anemia (29% v 20%, P=0.03), febrile neutropenia (25% v 14%, P=0.003), thrombocytopenia (34% v 13%, P < 0.001), and electrolyte abnormalities (5% v 2%, P=0.06).

Adverse events led to discontinuation in 12 patients in the R2-CHOP arm with cessation of lenalidomide alone in seven of these patients and discontinuation in four patients in the R-CHOP arm. There were nine treatment-related deaths with two in the R2-CHOP and seven in the R-CHOP arm.

ROBUST¹⁰
ROBUST is a large multicenter, international, double-blind, placebo-controlled phase III trial that compared R2-CHOP to R-CHOP in ABC-type DLBCL. Patients 18-80 years old with CD20 positive ABC-type DLBCL were included. Other inclusion criteria include performance status of two or less, at least stage II disease, and IPI score of two or more. Exclusion criteria con­sisted of prior lenalidomide exposure, CNS lymphoma, and transformed NHL. Patients were randomized in a 1:1 fashion to receive R2-CHOP or place­bo/R-CHOP for six cycles.

All patients received R-CHOP21 as defined above, with the exception of prednisone dosed at a flat dose of 100 mg. Patients either received lenalido­mide 15 mg oral on days 1-14 of every 21-day cycle if assigned to R2-CHOP, or placebo if assigned to R-CHOP. Addi­tionally, two additional rituximab doses (1 dose/21-day cycle) were permitted at cycles 7 and 8 if prespecified and considered standard of care per local practice. All patients were required to receive primary neutropenia prophylaxis with growth factor.

The primary endpoint was PFS for all randomized patients regardless of receiving study treatment. Secondary end points were event free survival (EFS), OS, response rates, duration of response (DOR), time to next lymphoma treatment, and safety.

There were 570 patients that met eligibility criteria in 21 countries from February 17, 2015 to August 3, 2017. Out of these 570 patients, 285 were randomized to receive either R2-CHOP or placebo/R-CHOP. The median age was 65 years. Eighty-eight percent of patients had stage III and IV disease with 34% having bulky disease. The median time from diagnosis or biopsy date to treatment was 31 days for both arms.

At the median follow-up time of 27.1 months, the primary endpoint of PFS was not met (HR, 0.85; P=0.29). The two-year PFS was 67% for R2-CHOP and 64% for placebo/R-CHOP. In exploratory subgroup analyses, there was a positive trend in two-year PFS for R2-CHOP for patients with IPI three or more, non-bulky disease, and baseline creatinine clearance 30 to < 60 mL/min. The secondary endpoint of EFS was also not met (HR, 1.04; P=0.73) in either arm. OS data was immature, but the estimated two-year OS rates were 79% for R2-CHOP arm and 80% for placebo/R-CHOP arm. ORR was 91% with CR rates of 69% for R2-CHOP arm and 65% for placebo/R-CHOP arm. The other secondary endpoints of time to next treatment and DOR were not reached.

For the safety analysis, patients that received at least one dose of any study treatment were included, which totaled to 283 R2-CHOP and 284 R-CHOP patients. There were 89% of R2-CHOP and 91% of placebo/R-CHOP patients that complet­ed six cycles of R-CHOP. Seventy-five percent of R2-CHOP and 84% of place­bo/R-CHOP patients completed both lenalidomide or placebo and R-CHOP.

Serious treatment-emergent AEs occurred in 37% of R2-CHOP and 31% of placebo/R-CHOP. The most common grade 3/4 AEs were neutropenia (60% vs 48%), anemia (22% v 14%), thrombocy­topenia (17% v 11%), leukopenia (14% v 15%), febrile neutro­penia (14% v 9%), and lymphopenia (11% v 8%) for R2-CHOP and placebo/R-CHOP, respectively. Treatment discontinuation occurred in 17% of R2-CHOP and 11% placebo/R-CHOP, primarily due to neutropenia. There were 119 patients that died during the study (20% R2-CHOP vs 22% placebo/R-CHOP) with the majority being caused by malignant disease or related complications.

CONCLUSION
The E1412 and ROBUST trials conflicted in terms of efficacy results but both showed no new safety concerns with treatment. E1412 showed benefit of R2-CHOP treatment in ABC-DLBCL whereas the larger ROBUST trial did not. However, both trials highlighted the addition of a novel agent to standard of care based on molecular classification. Further studies are warranted to evaluate novel agents in all molecular subsets of DLBCL.

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