FDA Approval Sought for Ibrutinib/Rituximab in Frontline CLL/SLL

Danelle James, MD, MAS, Imbruvica Clinical Development Lead, Pharmacyclics LLC

Danelle James, MD, MAS

A supplemental new drug application (sNDA) has been submitted to the FDA for ibrutinib (Imbruvica) for use in combination with rituximab (Rituxan) for the first-line treatment of patients ≤70 years old with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).¹

The sNDA is based on findings from the phase III E1912 trial, in which the combination demonstrated an 83% reduction in the risk of death compared with standard fludarabine, cyclophosphamide, and rituximab (FCR) after a median follow-up of 33.6 months (HR, 0.17; 95% CI, 0.05-0.54; P <.001)^2,3 Additionally, there was a 65% reduction in the risk of progression or death with Ibrutinib/rituximab versus FCR (HR, 0.35; 95% CI, 0.22-0.56; P <.001).

Moreover, safety data were consistent with the known tolerability of ibrutinib. Four-year follow-up findings of the phase III trial will be presented at the 2019 ASH Annual Meeting, AbbVie, which jointly develops ibrutinib with Janssen Biotech, Inc., stated in a press release.

"While therapeutic approaches in chronic lymphocytic leukemia have improved dramatically over the past several years, chemoimmunotherapy, which can often be an aggressive course for even those who are fit enough to tolerate it, has remained a standard of care for many previously untreated patients," Danelle James, MD, MAS, Imbruvica Clinical Development Lead, Pharmacyclics LLC, an AbbVie company, stated in the press release.

"We are pleased that the FDA recognizes the urgent need to bring a more efficacious treatment option to younger adult patients with CLL who are considered candidates for chemoimmunotherapy. We look forward to working closely with the agency during the review of the landmark phase III E1912 clinical trial data to bring the Imbruvica combination regimen to younger adult patients as quickly as possible."

The application is being reviewed as part of the FDA’s Real-Time Oncology Review program, which is designed to have a more efficient review process to make therapies more quickly available to patients.

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 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. AbbVie submits supplemental new drug application to U.S. FDA for Imbruvica® (ibrutinib) in combination with rituximab for the treatment of previously untreated, younger adults with chronic lymphocytic leukemia. AbbVie. Published November 8, 2019. https://prn.to/36OJsT9. Accessed November 8, 2019.
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—rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381:432-443. doi: 10.1056/NEJMoa1817073.