An updated analysis of obinutuzumab alone or in combination with chemotherapy for patients with treatment-naïve or relapsed/refractory chronic lymphocytic leukemia detected no new safety signals. Investigators in the phase IIIb GREEN trial also found overall response rates greater than 80% at 3 months post-treatment in some patients.
An updated analysis of obinutuzumab (Gazyva) alone or in combination with chemotherapy for patients with treatment-naïve or relapsed/refractory chronic lymphocytic leukemia (CLL) detected no new safety signals. Investigators in the phase IIIb GREEN trial (NCT01905943) also found overall response rates (ORR) greater than 80% at 3 months post-treatment in some patients.1
The incidence of grade 3 adverse events (AEs) was the primary outcome of interest. In results published inHaematologica, 79.2% (95% CI 75.8- 82.3) of patients treated in first-line and 82.4% (95% CI 77.9-86.3) of patients with relapsed/refractory disease experienced grade 3 AEs. At a median observation time of 24.5 months (range, 0.3-37.8), the rate of serious AEs was slightly higher in the relapsed/refractory group (50.6% vs 57.8%).
The most common (≥5) grade 3 AEs included neutropenia (49.9%), thrombocytopenia (16.4%), anemia (9.6%), and pneumonia (9.0%). The overall rate of serious AEs in the safety population (n = 971) was 53.1%, most often neutropenia (10.8%), pneumonia (9.5%), and febrile neutropenia (7.0%).
A total of 112 (11.5%) patients died during study. One hundred died during post-treatment follow-up and 12 within 28 days of last dose. AEs were the leading cause of death (n = 71; 7.3%). Patients with relapsed/refractory disease were more likely to die than patients treated in firstline (11.7% vs 4.9%).
The most common AEs leading to death were pneumonia (n = 12; 1.2%) and sepsis (n = 5; 0.5%).
Overall, 85.8% of AEs were considered to be related to obinutuzumab, most often neutropenia (40.2%), thrombocytopenia (22.6%), nausea (16.8%), pyrexia (23.2%), and anemia (11.1%).
“In the largest obinutuzumab patient cohort analyzed to date, the GREEN primary safety data were in line with the safety and tolerability profile previously observed in patients receiving obinutuzumab-based treatment for CLL,” wrote lead author Véronique Leblond, MD, head of the Department of Hematology at Pitié Salpêtrière Hospital, Paris, France, and colleagues wrote.
“Toxicities were generally manageable and response rates were encouraging in this broad population of CLL patients, including previously untreated, fit and unfit patients and those with R/R disease. Based on these data, future trials are warranted,” added Leblond et al.
Patients received 1000 mg of obinutuzumab, a glycoengineered type II anti-CD20 antibody, alone or in combination with investigator’s choice of fludarabine (Fludara) plus cyclophosphamide, chlorambucil (Leukeran), or bendamustine based on fitness. In cycle 1, treatment was split over the first 2 days, then administered on days 8 and 15. Treatment was administered on day 1 of cycles 2 to 6 for a total of six 28-day cycles.
In preliminary safety data of 825 patients presented in 2016, neutropenia (44.7%) was the most common grade 3 AE followed by thrombocytopenia (15.9%), anemia (9.0%), febrile neutropenia (6.9%), and leukopenia (6.2%).2
Eighty-three percent of patients developed AEs considered to be related to treatment with obinutuzumab including neutropenia (36.0%), thrombocytopenia (23.0%), pyrexia (21.7%), nausea (17.5%), chills (15.3%) and anemia (10.4%).
There was a total of 367 (44.5%) serious AEs recorded, and 32 (3.9%) fatal AEs.
In this updated analysis, the intent-to-treat (ITT) population included 972 patients recruited at 169 centers in 31 countries from October 2013 to 2016. The safety population includes 971 patients. A total of 630 (64.8%) patients were treatment-naïve and 341 had relapsed refractory disease. The treatment-naïve cohort included 339 (34.9%) fit patients and 291 (29.9%) unfit.
Investigators found that 78.5% (95% CI 73.7-82.7) of fit patients experienced grade 3 AEs compared with 80.1% (95% CI 75.0-84.5) of unfit patients. Fitness was defined as a Cumulative Illness Rating Scale (CIRS) score ≤6 and creatinine clearance (CrCl) ≥70 mL per minute. Patients in the unfit group had a CIRS score >6 and/or CrCl <70 mL per minute.
While rates of grade 3 AEs were similar between fit and unfit patients, the overall rate of serious AEs was higher in unfit patients (58.8% vs 43.7%).
The most common (≥20%) any-grade treatment-emergent adverse events (TRAEs) included neutropenia (58.4%), pyrexia (32.0%), thrombocytopenia (31.2%), nausea (27.8%) and anemia (23.7%).
A total of 227 (23.4%) patients had ≥1 any-grade cytopenia that appeared during the treatment period and persisted ≥24 days post-treatment. Twenty-three (2.4%) had ≥1 any-grade cytopenia that developed more than 24 days post-treatment.
Among treatment-naïve patients in the ITT population, ORR was 89.5% in the obinutuzumab/fludarabine/cyclophosphamide group compared with 82.4% for obinutuzumab/cholrambucil, 81.8% with obinutuzumab/bendustamine, and 63.5% for obinutuzumab monotherapy. The rates of complete response (CR)/CR with incomplete marrow recovery were 46.4%, 16.2%, 35.7%, and 20.6%, respectively.
In the relapsed/refractory population, ORR was 82.5% in the obinutuzumab/fludarabine/cyclophosphamide group compared with 54.3% for obinutuzumab/cholrambucil, 72.8% with obinutuzumab/bendustamine, and 42.2% for obinutuzumab monotherapy.
At the 2018 European Hematology Association Congress in June, investigators presented results from the final analysis of the phase III CLL11 trial (NCT01010061). That analysis showed that the combination of obinutuzumab plus chlorambucil (Leukeran) reduced the risk for death by 24% versus rituximab (Rituxan) plus chlorambucil in treatment-naïve patients with CLL with comorbidities.3
With a median follow-up of 59.4 months, the median overall survival was not reached in the obinutuzumab/chlorambucil arm compared with 73.1 months for rituximab/chlorambucil (HR, 0.76; 95% CI, 0.60-0.97;P<.0245).
The obinutuzumab combination also reduced the risk for disease progression or death by 51% compared with the rituximab regimen (28.9 vs 15.7 months; HR, 0.49; 95% CI, 0.41-0.58;P<.0001).
In May, AbbVie, manufacturer of ibrutinib (Imbruvica), announced topline results from the phase III iLLUMINATE trial (NCT02264574) showing that the ibrutinib/obinutuzumab combination met its primary result for progression-free survival for treatment-naïve patients with CLL or small lymphocytic lymphoma. The trial was designed to detect a “clinically and statistically significant difference in PFS” for ibrutinib/obinutuzumab compared with obinutuzumab alone.
Investigators in the United States are currently evaluating the ibrutinib/obinutuzumab combination in treatment-naïve patients with CLL in a phase Ib/II trial (NCT02315768). The research team plans to enroll 32 patients aged ≥65 years or who have comorbidities making them ineligible for chemotherapy-based treatment.
Obinutuzumab received FDA approval for use in combination with chlorambucil in patients with treatment-naïve CLL in 2013 based on prior results from CLL11. The agency approved obinutuzumab plus bendamustine for patients with follicular lymphoma (FL) who have received prior therapy in 2016. In 2017, the drug was approved for use in combination with chemotherapy followed by obinutuzumab alone for first-line treatment of advanced (FL).