Frontline ibrutinib + rituximab superior to gold standard for young patients with CLL
First-line therapy with the BTK* inhibitor ibrutinib plus the anti-CD20 immunotherapy rituximab confers significant survival advantage over the current gold-standard regimen of fludarabine, cyclophosphamide, and rituximab (FCR) for young, fit patients with treatment-naïve chronic lymphocytic leukaemia (CLL), according to the E1912 trial, a large cooperative group study supported by the US National Cancer Institute.
“Ibrutinib and rituximab provides superior PFS and OS** compared with FCR ... [and] was well tolerated in patients aged ≤70 years,” said study principal investigator Dr Tait Shanafelt from Stanford University in Stanford, California, US.
After a median follow-up of 33.6 months at the first interim analysis, the primary endpoint of PFS was significantly prolonged with ibrutinib + rituximab compared with FCR in both the intent-to-treat (ITT; hazard ratio [HR], 0.35; p<0.00001) and the per-protocol analyses (HR, 0,32; p<0.00001). [ASH 2018, abstract LBA-4]
According to Shanafelt, the between-group difference crossed the boundary for superiority. He also noted that the rates of PFS and OS for FCR group at 3 years were 73 percent and 92 percent, respectively in the current study, which are identical to those observed in the previous GCLLSG CLL10 study which enrolled a similar patient population (70 percent for PFS and 90 percent for OS). “This suggests that FCR performed as expected in the current study,” he said.
Moreover, PFS benefit was seen across subgroups regardless of age, gender, performance status, disease stage, and the presence of splenomegaly.
Importantly, as Shanafelt pointed out, PFS benefit was also seen with ibrutinib + rituximab in the subgroup with unmutated IgVH*** status (HR, 0.26; p<0.00001), which has been associate with a poorer prognosis compared with mutated IgVH. Although the risk of disease progression or death was also lower with ibrutinib + rituximab vs FCR in the IgVH-mutated subgroup, the difference between groups was smaller and not statistically significant (HR, 0.44; p=0.07).
In addition, OS was significantly longer with ibrutinib + rituximab than FCR in the ITT population (HR, 0.17; p<0.0003) as well as the per-protocol population (HR, 0.13; p<0.0001).
In terms of safety, the combination therapy of ibrutinib + rituximab was associated with fewer grade ≥3 AEs (58.5 percent vs 72.1 percent; p=0.004). In particular, there were significantly lower rates of grade ≥3 neutropenia, anaemia, thrombocytopenia, and any infection (p<0.001 for all) in the ibrutinib + rituximab group vs the FCR group. “Ibrutinib and rituximab was well tolerated in patients ≤70 years,” said Shanafelt.
The phase III study randomized 529 patients aged ≤70 years (median age 58 years, 32.7 percent female) with untreated CLL (63.3 percent ECOG performance status=0, 71.1 percent IgVH unmutated) in a 2:1 ratio to receive either a combination regimen of ibrutinib (420 mg/day until disease progression) and rituximab (50 mg/m2 on day 1 of cycle 2; 325 mg/m2 on day 2 of cycle 2 followed by 500 mg/m2 on day 1 of cycles 3–7) or six cycles of intravenous FCR# every 28 days. Patients with IgVH 17p deletion were excluded due to known poor disease response to FCR.
“CLL is one of the most common lymphoid malignancies, accounting for 11 percent of lymphoid neoplasms,” said Shanafelt. “The need for indefinite therapy should be evaluated in future clinical trials testing novel agent combination therapy.”