Final Analysis of GOYA: A Randomized, Open-Label, Phase III Study of Obinutuzumab or Rituximab Plus CHOP in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma

Introduction: The standard first line treatment for diffuse large B-cell lymphoma (DLBCL) is rituximab (R) plus CHOP (R-CHOP). However, approximately 35-40% of patients (pts) relapse following such treatment, and outcomes with salvage therapy remain poor. Obinutuzumab (GA101; G) is a fully humanized, glycoengineered, type II anti-CD20 monoclonal antibody. It has demonstrated greater direct cell death induction and antibody-dependent cellular cytotoxicity/phagocytosis activity than R, and has shown activity and an acceptable safety profile when combined with CHOP (G-CHOP) in first-line treatment of pts with advanced DLBCL (Sharman et al. Leuk Lymphoma 2019). GOYA (NCT01287741) was a randomized, open-label, multicenter Phase III study that compared the efficacy and safety of G-CHOP with R-CHOP in pts with previously untreated DLBCL. In the primary analysis (median observation period: 29 months), G-CHOP did not significantly improve investigator (INV)-assessed progression-free survival (PFS) compared with R-CHOP (Vitolo et al. J Clin Oncol 2017). Here, we present results from the final analysis of GOYA.

Methods: Pts were aged ≥18 years, had histologically documented, previously untreated, CD20-positive DLBCL, with adequate hematologic function, ≥1 bi-dimensionally measurable lesion, an ECOG performance status of ≤2, and were classified as being in an International Prognostic Index (IPI) risk group of high, high-intermediate, or low-intermediate risk. Low-risk pts with an IPI score of 1 (not due to age alone) or 0 with bulky disease (1 lesion ≥7.5cm) were also eligible. Pts were randomized (1:1) to 8 (21-day) cycles of G (1000mg i.v. on Days [D]1, 8 and 15, Cycle [C]1 and D1, C2-8) or R (375mg/m² i.v. on D1, C1-8) in combination with 6 or 8 cycles of CHOP. Preplanned radiotherapy was allowed for bulky or extranodal disease. The primary endpoint was INV-assessed PFS. Secondary endpoints included independent review committee-assessed PFS (primary analysis only); overall survival (OS); complete response (CR) and overall response rate (ORR) with or without PET (according to modified Cheson 2007 criteria); event-free survival; disease-free survival; duration of response; time to next anti-lymphoma treatment; PFS according to cell of origin (COO; germinal center B cell [GCB] or activated B cell [ABC]), as an exploratory endpoint; and safety.

Results: In total, 1418 pts were randomized in GOYA; of these, 704 pts who received G-CHOP and 710 who received R-CHOP were included in this final analysis (clinical cut-off date: January 31, 2018). Overall median follow-up was 47.7 months. Baseline characteristics were well balanced between the G-CHOP and R-CHOP arms. INV-assessed PFS was similar between G-CHOP and R-CHOP (5-year PFS, 63.8% vs 62.6%; stratified HR, 0.94; 95% CI: 0.78, 1.12; p=0.48; Table). There was no significant difference in 5-year OS between the G-CHOP and R-CHOP groups (77.0% vs 77.7%) or in CR or ORR (Table). In the subgroup analysis of pts with ABC, GCB and unclassified DLBCL, no significant reductions in risk of disease progression were observed (stratified HR for INV-PFS, 0.91 [95% CI: 0.61, 1.36], 0.80 [95% CI: 0.58, 1.12] and 1.10 [95% CI: 0.65, 1.88], respectively). No new safety signals were identified. Grade ≥3 adverse events (AEs; 75% vs 66%) and serious AEs (44% vs 38%) were more common with G-CHOP than R-CHOP. Grade ≥3 AEs of particular interest (≥2% of pts in either treatment arm) were more frequent in the G-CHOP arm: infusion-related reactions (10% vs 3%), neutropenia (57% vs 47%), infections (20% vs 16%), cardiac events (5% vs 3%), thrombocytopenia (6% vs 2%), and hemorrhagic events (3% vs 1%); secondary malignancies occurred in 3% and 2% of the R-CHOP and G-CHOP arms, respectively. AEs resulting in treatment withdrawal (12% [87/702] G-CHOP; 8% [58/701] R-CHOP) and AEs with fatal outcome (6% [43/702] G-CHOP; 4% [31/701] R-CHOP) were slightly more common with G-CHOP. The most common grade 5 AEs were pneumonia (n=5 both arms) and sepsis/septic shock (G-CHOP, n=7; R-CHOP, n=3).

Conclusions: Consistent with the primary analysis, G-CHOP did not significantly improve INV-assessed PFS compared with R-CHOP in previously untreated pts with DLBCL. Furthermore, there was no significant difference in 5-year OS between the treatment arms. No unexpected safety signals were identified. Further investigation of outcomes is ongoing, including the prognostic value of COO and BCL2 positivity.

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