Ibrutinib/Rituximab Improves OS, PFS Versus FCR for Untreated CLL

Tait D. Shanafelt, MD

The combination of ibrutinib (Imbruvica) and rituximab (Rituxan) significantly improved overall survival (OS) and progression-free survival (PFS) compared with standard fludarabine, cyclophosphamide, and rituximab (FCR) for younger patients with chronic lymphocytic leukemia (CLL), according to findings from the phase III E1912 study presented at the 2018 ASH Annual Meeting.

After a median follow-up of 33.4 months, there was a 65% reduction in the risk of progression or death with Ibrutinib/rituximab compared with FCR (HR, 0.35; 95% CI, 0.22-0.50; P <.00001). Moreover, ibrutinib/rituximab reduced the risk of death by 83% compared with FCR (HR, 0.17; 95% CI, 0.05-0.54; P <.0003). Treatment-related grade 3/4 adverse events (AEs) were significantly lower with the BTK inhibitor combination compared with FCR (58.5% vs 72.1%, respectively; P = .004).

"There is a remarkably lower risk of death in patients receiving the new therapy in comparison with standard chemotherapy," said lead investigator Tait D. Shanafelt, MD, from Stanford University. "I would emphasize that the new therapy is also less toxic than our historical therapy. Obviously, in cancer trials we want to improve the effectiveness or reduce the side effects. This trial is one of the rare circumstances where we've done both with a single therapy."

In the study, 354 patients received the combination of ibrutinib and rituximab and 175 received FCR. Throughout the trial, ibrutinib was administered at 420 mg orally on days 1 to 28 until progression. In cycle 1, patients received ibrutinib alone and in cycle 2 patients were administered ibrutinib with rituximab at 50 mg/m² intravenously (IV) on day 1 and at 325 mg/m² on day 2. For cycle 3 to 7, rituximab was given at 500 mg/m2 IV on day 1 along with baseline ibrutinib. FCR was given at the standard dose for 6 cycles.

Across all patients enrolled, the median age of patients was 58 years, with 40.6% of patients ≥60 years of age. A third of patients were female (32.7%), and two-thirds of patients had ECOG performance status of 0 (63.3%). IGHV was unmutated for 71.1% of patients, 22.2% had an 11q deletion, 18.3% trisomy 12, and 33.8% deletion 13q. Patients were split between Rai stages, with 43.1% having stage III/IV disease.

The improvement in PFS seen with the combination of ibrutinib and rituximab was experienced by patients across all subgroups. In this with IGHV unmutated status, there was a 74% reduction in the risk of progression or death with ibrutinib/rituximab versus FCR (HR, 0.262; 95% CI, 0.137-0.498; P <.0001). However, a statistically significant benefit was not observed for patients with IGHV mutations, although a trend was observed (HR, 0.435; 95% CI, 0.140-0.1350; P = .07).

"The novel therapy is improving disease control, with longer progression-free survival," said Shanafelt. "This establishes ibrutinib-based therapy as the most effective treatment tested to date for untreated patients."

Ibrutinib/rituximab demonstrated a preferential toxicity profile compared with FCR, with significantly fewer treatment-related grade ≥3 AEs for neutropenia (22.7% vs 43.7%, respectively), anemia (2.6% vs 12%), thrombocytopenia (2.9% vs 13.9%), and neutropenic fever (2.3% vs 15.8%). Other grade ≥3 treatment-related AEs of interest for ibrutinib/rituximab versus FCR, respectively, included infection (5.4% vs 8.2%), diarrhea (2.6% vs 0.6%), hypertension (7.4% vs 1.9%), bleeding (1.1% vs 0.0%), and atrial fibrillation (2.9% vs 0.0%).

"FCR is a therapy with high side effects and cannot be tolerated by all CLL patients, and it primarily is given to those age 70 or younger," said Shanafelt. "This new regimen is well-tolerated and had fewer side effects than our previous standard therapy."

Across studies exploring ibrutinib, the BTK inhibitor was given until progression; however, new clinical trials are beginning to explore if ibrutinib can be given for a fixed duration and whether newer combinations are more effective, Shanafelt noted.

The phase III EA9161 trial is examining the combination of ibrutinib with obinutuzumab and venetoclax. In this study, treatment will be stopped after 19 cycles, if there is no disease progression (NCT03701282). Another phase III study (A041702) is looking at the same combination with the duration of therapy based upon the minimal residual disease response achieved (NCT03737981). Both studies are currently enrolling.

Shanafelt TD, Wang V, Kay NE, et al. A Randomized Phase III Study of Ibrutinib (PCI-32765)-Based Therapy Vs. Standard Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL): A Trial of the ECOG-ACRIN Cancer Research Group (E1912). Presented at: 2018 ASH Annual Meeting; December 1-4, 2018; San Diego. Abstract LBA-4.

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