A randomized, open-label, Phase III study of obinutuzumab or rituximab plus CHOP in patients with previously untreated diffuse large B-Cell lymphoma: final analysis of GOYA

Rituximab (R) in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) is the current standard of care for diffuse large B cell lymphoma (DLBCL) [1‐3]. Despite treatment with R-CHOP, many patients’ relapse and outcomes remain poor with salvage therapies [4]. Obinutuzumab (GA101; G) is a fully humanized, glycoengineered, type II anti-CD20 monoclonal antibody which has shown greater direct cell death induction, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis than R [5‐8].

In a Phase II study in patients with advanced DLBCL, G demonstrated promising activity and an acceptable safety profile when combined with CHOP (G-CHOP) as a first-line treatment [9]. GOYA (NCT01287741) was a randomized, open-label, multicenter Phase III study that evaluated the efficacy and safety of G-CHOP compared with R-CHOP in patients with previously untreated DLBCL. Results from the primary analysis (clinical cut-off date, 29 April 2016), which had a median observation period of 29 months, showed that G-CHOP did not significantly improve investigator-assessed progression-free survival (PFS) compared with R-CHOP [10]. Here, we present the updated results from the final analysis of GOYA.

The study design and methodology of the GOYA study are described in full elsewhere [10]. In brief, patients were included if they were at least 18 years of age and had histologically documented, previously untreated, CD20-positive DLBCL; adequate hematologic function; ≥ 1 bi-dimensionally measurable lesion; an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2; and an International Prognostic Index (IPI) risk group of high, high-intermediate, or low-intermediate risk. Low-risk patients with an IPI score of 1 (not due to age alone) or 0 with bulky disease (1 lesion ≥ 7.5 cm) were also eligible. Using stratified permuted block randomization, patients were randomized 1:1 to eight (21 days) cycles of G (1000 mg intravenous injection [IV] on days 1, 8 and 15, cycle 1 and day 1, cycles 2–8) or R (375 mg/m² IV on day 1 of cycles 1–8) in combination with six or eight cycles of CHOP. The randomization stratification factors were number of planned cycles of CHOP, IPI score, and geographic region. Pre-planned radiotherapy was allowed for bulky or extranodal disease. The primary endpoint was investigator-assessed PFS. Secondary endpoints included independent review committee (IRC)-assessed PFS (primary analysis only); overall survival (OS); complete response (CR) and overall response rate (ORR) according to the modified Cheson 2007 criteria [11] by computed tomography (CT) and CT incorporating positron emission tomography (PET); event-free survival (EFS; defined as the period from the date of randomization until the date of disease progression, relapse, initiation of a new non-protocol-specified anti-lymphoma treatment, or death from any cause); disease-free survival (DFS; defined as the percentage of patients with CR at the end of treatment); time to next anti-lymphoma treatment; and safety. An exploratory endpoint of investigator-assessed PFS according to cell of origin (COO; germinal center B cell [GCB] or activated B cell [ABC]) based on gene expression profiling using the NanoString Research-Use-Only assay (NanoString Technologies, Inc., Seattle, WA) [12, 13] was also analyzed.

This Phase III, open-label, randomized study was designed to compare the efficacy and safety of G-CHOP versus R-CHOP in previously untreated patients with DLBCL. In agreement with the findings of the primary analysis (clinical cut-off date, 29 April 2016) [10], results of this analysis did not demonstrate superiority of G-CHOP compared to R-CHOP.

After a median observation time of 47.7 months, investigator-assessed PFS (study primary endpoint) did not differ significantly between G-CHOP and R-CHOP (stratified HR 0.94, 95% CI 0.78–1.12; p = 0.48), with similar results to those obtained in the primary analysis (stratified HR 0.92, 95% CI 0.76–1.11; p = 0.39). The results of the secondary endpoints were consistent with the primary endpoint and did not show a benefit of G-CHOP over R-CHOP. The 5-year OS rates were similar for G-CHOP and R-CHOP (77.0% vs 77.7%).

G-chemotherapy has previously demonstrated superiority compared with R-chemotherapy in studies of patients with other B cell malignancies, such as follicular lymphoma (FL) and chronic lymphocytic leukemia [14, 15]. The lack of superior efficacy of G-CHOP compared with R-CHOP observed within this study was unexpected.

In the present study, we noted a trend towards a PFS benefit with G-CHOP versus R-CHOP in patients with GCB DLBCL. Like FL, GCB DLBCL is derived from germinal center B cells, and many driver genetic alterations that provide a selective advantage and contribute to cancer development are seen in both lymphomas [16]. This may, in part, explain the trend in benefit observed in the patients with GCB DLBCL, which is consistent with the improvement in outcome seen in patients with FL when treated with G-CHOP versus R-CHOP [14]. Interestingly, we found that the ABC DLBCL subgroup was associated with better PFS (5-year Kaplan–Meier PFS estimates: G-CHOP 54.3% and R-CHOP 55.7%) than reported in retrospective population analyses of previously untreated patients with DLBCL treated with R-CHOP (5-year Kaplan–Meier PFS estimates: R-CHOP 46% [17] and 48% [18]). This result may indicate a selection bias for low-risk patients in the GOYA trial, with very high-risk patients requiring urgent treatment less likely to be enrolled into a prospective trial such as this. It is noteworthy that the total median time from diagnosis to randomization was 24.0 days (range, 1.0–1104.9). While it is unclear how selection bias may have affected the overall result, there was no significant improvement in outcome with G-CHOP in any IPI subgroup.

The frequency and nature of the AEs reported were as expected for the patient population and the treatment regimens being assessed, and no new safety signals were observed during the additional follow-up after the primary analysis. Higher rates of grades 3–5 and serious AEs occurred in the G-CHOP arm compared with the R-CHOP arm; however, these were generally clinically manageable. A similar percentage of deaths occurred in the G-CHOP and R-CHOP arms (21.2% vs 20.1%), and the majority of these fatalities were due to disease progression (12.4% vs 13.1%). There were no unexpected delayed toxicities observed, and a similar number of second malignancies occurred in the G-CHOP and R-CHOP arms (3.1 and 3.7%, respectively). A higher frequency of late-onset neutropenia was observed in the G-CHOP arm compared with the R-CHOP arm (8.7% vs 4.9%, respectively).

In conclusion, the final analysis of this study demonstrated that G-CHOP did not show a PFS benefit over R-CHOP in previously untreated patients with DLBCL, and R-CHOP remains the standard of care in this population. The results of the secondary endpoints were consistent with the primary endpoint. Overall, no unexpected safety findings were observed, and the toxicity of G-CHOP was generally manageable. Exploratory analyses and investigations of biomarkers are ongoing to evaluate whether there may be a role for G in identifiable subgroups of DLBCL.