A supplemental New Drug Application for the combination of ibrutinib and rituximab has been submitted to the FDA for the first-line treatment of patients aged 70 years or younger with chronic lymphocytic leukemia or small lymphocytic lymphoma, according to a press release from ibrutinib developer, AbbVie.
A supplemental New Drug Application (sNDA) for the combination of ibrutinib (Imbruvica) and rituximab (Rituxan) has been submitted to the FDA for the first-line treatment of patients aged 70 years or younger with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma, according to a press release from ibrutinib developer, AbbVie.1
The sNDA submission was prompted by results from the phase III E1912 study (NCT02048813) of ibrutinib plus rituximab or chemoimmunotherapy with the combination of fludarabine, cyclophosphamide, and rituximab. The first interim analysis of E1912 showed 77 progression-free survival (PFS) events and only 14 deaths. Patients in the ibrutinib/rituximab arm had a better PFS benefit than patients who got chemoimmunotherapy (HR, 0.352; 95% CI, 0.223-0.558;P<.0001). The combination of ibrutinib and rituximab also resulted in a higher overall survival (OS) than was seen with chemoimmunotherapy (HR, 0.168; 95% CI, 0.053-0.538; P= .0003).2
The study included a subgroup analysis comparing PFS in both arms based on age, sex, performance status, disease stage or the presence/absence of del11q23. The analysis showed ibrutinib/rituximab to be superior to fludarabine/cyclophosphamide/rituximab. For patients withIGHV-unmutated disease, ibrutinib/rituximab showed better PFS (HR, 0.262; 95% CI, 0.137-0.498;P<.0001); however, chemoimmunotherapy resulted in better PFS inIGHV-mutated patients.
In the ibrutinib/rituximab arm, 58% of patients had grade 3/4 treatment-related adverse events (TRAEs). High-grade toxicities were more prominent in patients who received fludarabine/cyclophosphamide/rituximab (72%). ThePvalue was 0.0042. The most common grade 3/4 TRAE was neutropenia, which occurred in 23% of patients treated with ibrutinib plus rituximab (n = 80) and 44% of patients who received chemoimmunotherapy (n = 69;P<.0001). Infectious complications were also common TRAEs in both arms and occurred in 7.1% of patients who had ibrutinib/rituximab (n = 25) versus in 17.7% of patients who had chemoimmunotherapy (n = 28;P<.0001).
Low-grade TRAEs also occurred in both groups. For patients who received the ibrutinib combination or chemoimmunotherapy, respectively, there was infection (5.4% vs 8.2%), hypertension (7.4% vs 1.9%), atrial fibrillation (2.9% vs 0.0%), diarrhea (2.6% vs 0.6%), and bleeding (1.1% vs 0.0%).
The design of the study was a 2:1 randomization to either ibrutinib (420 mg/day), which was taken until disease progression with escalating doses of rituximab over a 7-day period, or 6 courses of intravenous fludarabine (25 mg/m2), cyclophosphamide (250 mg/m2) on days 1 to 3, with rituximab (50 mg/m2), every 28 days. The accrual goal was 519 patients; however, 529 patients were actually enrolled. The key primary end point was PFS and the key secondary end point was OS. The study also evaluated, change in the quality of life (QOL), the incidence of toxicity, change in FACT-Leu TOI score after 3 months and 6 months of therapy, the impact of CLL on QOL, and adherence to prescription assessed by the Moriskey Adherence Scale in the ibrutinib/rituximab arm.
Patient enrollment criteria were based on the National Cancer Institute and Internal Workshop on CLL criteria and SLL criteria from the World Health Organization. These patients could not have had prior chemotherapy or treatment with a Bruton’s kinase inhibitor or monoclonal antibody. Another requirement was an Eastern Cooperative Oncology Group performance status of 0 to 2, and a life expectancy of 12 months or more. Individuals with preexisting infectious diseases like HIV, and hepatitis C, and those with blood disorders and gastrointestinal diseases were excluded from the trial. Patients who were actively taking other investigational drugs were also excluded.
The study aimed to show that offering chemoimmunotherapy as the standard of care is not sufficient for some patients because the treatment is aggressive.
"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, AbbVie, stated in a press release.
From the study data, which was presented at the 2018 ASH Annual Meeting, investigators concluded that ibrutinib plus rituximab promotes superior PFS and OS compared with the chemoimmunotherapy combination of fludarabine, cyclophosphamide, and rituximab. Additionally, investigators believe that ibrutinib/rituximab may be a practice-changing combination for the frontline treatment of patients with CLL.
As a single-agent ibrutinib is FDA approved in 6 malignancies, including CLL. It is also being studied in combination with obinutuzumab (Gazyva) and venetoclax (Venclexta) for younger patients with CLL in the phase EA9161 study (NCT03701282), and the combination was givenpriority reviewby the FDA in 2018. Thephase II CLARITY studyis evaluating the tolerability of ibrutinib plus venetoclax in relapsed or refractory CLL.
The FDA has already begun reviewing the sNDA for ibrutinib/rituximab under Real-Time Oncology Review, a pilot program that allows the FDA to access trial data before an sNDA is officially submitted.
“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," said James in the press release.