Continued survival benefit at 5 years with frontline obinutuzumab in CLL
A combined regimen of obinutuzumab (a type II anti-CD20 antibody) and chlorambucil shows significant long-term survival benefit over rituximab plus chlorambucil or chlorambucil alone in patients with chronic lymphocytic leukaemia (CLL) and comorbidities who have not been treated previously, according to the final analysis of the CLL11* study presented at EHA 2018.
“These findings strongly suggest obinutuzumab be the preferred CD20 antibody when combined with chlorambucil … [and] support the use of obinutuzumab plus chlorambucil as front-line therapy in patients with CLL and comorbidities,” said lead author Dr Valentin Goede of the University Hospital of Cologne in Cologne, Germany.
After a median follow-up of 59.4 months (~5 years), obinutuzumab + chlorambucil significantly improved overall survival (OS) compared with rituximab + chlorambucil (median, not reached vs 73.1 months, hazard ratio [HR], 0.76; p=0.0245). The survival rates at 5 years were 66 percent vs 57 percent, respectively. [EHA 2018, abstract S151]
Median progression-free survival (PFS) was 28.9 months in the obinutuzumab + chlorambucil arm compared with 15.7 months in the rituximab + chlorambucil arm (HR, 0.49; p<0.0001) — representing a 51 percent reduction in risk of disease progression or death with obinutuzumab.
The survival benefit seen translated into a clinically meaningful improvement in the time to next treatment (TTNT), in favour of the obinutuzumab combination (56.4 vs 34.9 months, HR 0.58; p<0.0001).
“Obinutuzumab + chlorambucil prolonged TTNT relative to rituximab + chlorambucil by ~1.5 years, attaining an absolute treatment-free duration of ~4 years,” said Goede.
The open-label phase III CLL11 trial randomized 781 treatment-naïve patients (mean age 73 years) with CLL and comorbidities (CIRS** score, 8; CrCl***, 62 mL/min) 1:2:2 to receive six 28-day cycles of chlorambucil, rituximab + chlorambucil, or obinutuzumab + chlorambucil. Oral chlorambucil 0.5 mg/kg was given on days 1 and 15 throughout all cycles. Intravenous rituximab was administered at a dose of 375 mg/m2 on day 1 during the first cycle and at 500 mg/m2 on day 1 of subsequent cycles. Intravenous obinutuzumab 1000 mg was administered on days 1 (split over 2 days: 100 mg on day 1, 900 mg on day 2), 8, and 15 during the first cycle, and subsequently on day 1 of the remaining cycles.
Compared with chlorambucil alone, obinutuzumab + chlorambucil also showed significant improvements in terms of OS (median, not reached vs 66.7 months, HR, 0.68; p=0.0196), PFS (median, 31.1 vs 11.1 months, HR, 0.21; p<0.0001), and TTNT (median, 55.7 vs 15.1 months, HR, 0.25; p<0.0001).
The overall safety profile was consistent with the results from previous analyses, with no new safety signals detected for adverse events (AEs) of any grade or serious AEs, as well as late-onset toxicity. The most frequently reported fatal AEs (grade 5) were secondary malignancies and infections, which were more common in the immunotherapy arms than the chemotherapy alone arm, although these were rare. Fewer deaths occurred in the obinutuzumab combination arm compared with the rituximab combination arm (37 percent vs 45 percent), with disease progression being the most common cause of death (10 percent vs 15 percent).
“Obinutuzumab + chlorambucil provides clinically meaningful benefits in CLL patients with comorbidities … while maintaining an acceptable and manageable safety profile,” said Goede. “We can conclude that in the treatment landscape of CLL, obinutuzumab + chlorambucil is a valid and beneficial frontline therapy in unfit patients.”
“The quality of CD20 targeting is an important principal and prognostically relevant in CLL … the second-generation antibody gets better results and should be considered over type 1 antibodies [such as rituximab],” he continued. “Therefore, optimized CD20 targeting using obinutuzumab and a new combined regimen makes great sense.”