FDA Approves Ibrutinib/Rituximab for Frontline CLL/SLL

The FDA has approved an expanded indication of ibrutinib (Imbruvica) for use in combination with rituximab (Rituxan) for the frontline treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).¹

The approval is based on findings from the phase III E1912 trial, results of which showed a statistically significant improvement in PFS for patients receiving the combination of ibrutinib and rituximab compared with those receiving standard fludarabine, cyclophosphamide, and rituximab (FCR; HR, 0.34; 95% CI, 0.22-0.52; P <.0001).² At a median follow-up of 37 months, the median PFS was not reached in either arm.

Moreover, safety data were consistent with the known tolerability of ibrutinib. Four-year follow-up findings of the phase III trial were presented at the 2019 ASH Annual Meeting, which showed that, after a median follow-up of 48 months, results continued to favor the combination over FCR for PFS (HR, 0.39; 95% CI, 0.26-0.57; P <.0001).³ At 3 years, the combination showed a 65% reduction in the risk of disease progression or death (HR, 0.35; 95% CI, 0.22-0.56; P <.001), and the 3-year PFS rates were 89.4% in the ibrutinib/rituximab arm versus 72.9% in the FCR arm.⁴

The HR for overall survival (OS) also favored IR over FCR (HR, 0.34; 95% CI, 0.15-0.79; P = .009). The 3-year OS rates were 99% in the IR arm compared with 93% in the FCR arm.

The review of the supplemental new drug application (sNDA) was conducted under Project Orbis, which is an initiative of the FDA Oncology Center of Excellence and provides a framework for concurrent submission and review of oncology drugs among international partners. For this sNDA, a modified Project Orbis was used because of the timing of submission to other regulatory agencies. The FDA is collaborating with the Australian Therapeutic Goods Administration, Health Canada, and Swissmedic as they review the application.

In the study, which was conducted by the ECOG-ACRIN Cancer Research Group and sponsored by the National Cancer Institute, 529 patients ≤70 years old with previously untreated CLL were randomized 2:1 to receive the combination of ibrutinib and rituximab (n = 354) or FCR (n = 175).

Ibrutinib was administered at 420 mg orally on days 1 to 28 until disease 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 was 58 years, with 40.6% of patients ≥60 years of age. About one-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 primary endpoint was progression-free survival (PFS); overall survival (OS) was a secondary endpoint.

Additional findings showed that the 3-year PFS rates were 89.4% and 72.9% with ibrutinib/rituximab and FCR, respectively. The 3-year OS rate was 98.8% with the ibrutinib regimen and 91.5% with FCR.

The improvement in PFS seen with the combination of ibrutinib and rituximab was experienced by patients across all subgroups. In those with IGHV unmutated status, there was a 74% reduction in the risk of progression or death with ibrutinib/rituximab versus FCR (HR, 0.26; 95% CI, 0.14-0.50), and the 3-year PFS rate was 90.7% and 62.5%, respectively. However, in patients with IGHV mutations, the 3-year PFS rate was 87.7% with ibrutinib/rituximab and 88.0% with FCR (HR, 0.44; 95% CI, 0.14-1.36).

Regarding safety, the rate of grade ≥3 AEs was similar between the 2 arms, but grade ≥3 infectious complications were lower with ibrutinib/rituximab (10.5%) versus FCR (20.3%; P <.001); grade 3/4 neutropenia was also lower in the ibrutinib arm than with FCR (25.6% vs 44.9%; P <.001). However, grade 3/4 hypertension was higher with ibrutinib/rituximab (18.8%) compared with FCR (8.2%; P = .002). Grade ≥3 hemorrhagic events occurred in 4 patients receiving ibrutinib/rituximab and in 0 patients on FCR (P = .32), and grade ≥3 cardiac toxic events occurred in 23 patients on ibrutinib plus rituximab and in 3 patients on FCR. There were 4 deaths on the ibrutinib/rituximab arm and 10 deaths on the FCR arm.

In the data presented at the 2019 ASH Annual Meeting,

In August 2018, the FDA approved the combination of ibrutinib and rituximab as a treatment option across all lines of therapy for patients with Waldenström macroglobulinemia.

References

1. FDA approves ibrutinib plus rituximab for chronic lymphocytic leukemia. FDA. Published April 21, 2020. https://bit.ly/2VRsWgu. Accessed April 21, 2020.
2. 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). Blood. 2018;132(suppl 1): LBA-4. doi: 10.1182/blood-2018-120779.
3. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib and rituximab provides superior clinical outcome compared to FCR in younger patients with chronic lymphocytic leukemia (CLL): extended follow-up from the E1912 Trial. Presented at 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 33. bit.ly/36999N2.
4. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib—rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381:432-443. doi: 10.1056/NEJMoa1817073.