Frontline Ibrutinib Showcases Long-Term OS Benefit in Older Patients With CLL

Alessandra Tedeschi MD

Frontline therapy with ibrutinib (Imbruvica) was successfully administered for more than 60 months in patients with chronic lymphocytic leukemia (CLL) aged 65 years and older and provided improved progression-free and overall survival (OS) compared with chlorambucil, according to long-term findings of the phase III RESONATE-2 trial presented at the 2019 European Hematology Association Congress.

After long-term follow-up of median 5 years (range, 0.1-66 months), progression-free survival (PFS) continued to favor ibrutinib over chlorambucil (HR, 0.15; 95% CI, 0.10-0.22). Moreover, PFS estimates at 5 years were 70% for ibrutinib-treated patients compared with 12% in those who received chlorambucil (HR, 0.146; 95% CI, 0.098-0.218).

OS also favored ibrutinib with 60 months of follow-up; OS rates were 83% with ibrutinib compared with 68% with chlorambucil (HR 0.45; 95% CI, 0.266-0.761), with crossover on progression to ibrutinib by 57% of patients receiving chlorambucil.

“As ibrutinib is given as continuous therapy, long-term efficacy and safety data are critical to inform clinical practice,” said lead study author Alessandra Tedeschi MD, Department of Hematology, Azienda Ospedaliera Niguarda Ca’ Granda in Milan, Italy, in a presentation during the meeting. “It is also important to know the long-term safety on ibrutinib in older patients, as the average age of diagnosis of CLL is 72 years.”

Tedeschi presented findings after 5 years of follow-up with ibrutinib in older patients with CLL or small lymphocytic lymphoma (SLL) who were enrolled in the open-label, international, randomized, phase III RESONATE-2 (NCT01722487, extension NCT01724346) trial.

Ibrutinib is a first-in-class BTK inhibitor that has been FDA approved for a number of indications in CLL: in those who have received ≥1 prior therapy, in adult patients with 17p deletion, for treatment-naïve patients, in combination with bendamustine and rituximab (Rituxan) in adult patients with CLL/SLL, and in combination with obinutuzumab (Gazyva) for treatment-naïve patients with CLL/SLL.

The RESONATE-2 trial, which was the basis for the BTK inhibitor’s frontline approval, compared the efficacy and safety of first-line ibrutinib with chlorambucil in 269 patients aged ≥65 years with previously untreated CLL/SLL and without 17p deletion. Patients were randomized 1:1 to oral ibrutinib at 420 mg (n = 136) once daily continuously until disease progression or unacceptable toxicity or to standard chlorambucil, (n = 133) at 0.5 to 0.8 mg/kg for up to 12 cycles. Patients in the ibrutinib and chlorambucil arms had a median age of 73 and 72 years, and 71% versus 70% were aged ≥70 years, respectively. Approximately 62% of patients in the respective arms were male and 44% versus 41% of patients had an ECOG performance score of 0.

The study endpoints were PFS, OS, overall response rate (ORR), and safety. Efficacy was evaluated by the investigators according to International Workshop on Chronic Lymphocytic Leukemia (2008) criteria with modification.

Results showed that the ORR was 92%, which included patients achieving complete response (CR) and partial response with lymphocytosis (CR/CRi). The CR/CRi rate increased over time from 11% at the primary analysis at a median follow-up of 18 months to 30% at 60 months of follow-up.

“Responses with ibrutinib improved over time with nearly three-fold more patients achieving CR/CRi with long-term follow up,” Tedeschi commented. Improved survival with ibrutinib was also observed in a subgroup of patients with high-risk genomics, defined as unmutated IGHV, 11q deletion, and/or TP53 mutation, where PFS was prolonged with ibrutinib compared with chlorambucil (HR, 0.08; 95% CI, 0.05-0.15) and OS was also improved (HR, 0.37; 95% CI, 0.18-0.74), respectively. Specifically, PFS was better with ibrutinib compared with chlorambucil in patients with unmutated immunoglobulin heavy chain variable region (IGHV; HR, 0.11; 95% CI, 0.06-0.19) and in patients with 11q deletion (HR, 0.03; 95% CI, 0.01-0.11).

No new safety signals emerged with long-term ibrutinib treatment. The most commonly reported grade ≥3 adverse events (AEs) with ibrutinib were neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), hyponatremia (6%), atrial fibrillation (5%), and cataract (5%).

The rates of most AEs decreased with longer treatment duration, as did dose reductions due to grade ≥3 AEs. During treatment years 0 to 1, grade ≥3 AEs occurred in 5% of patients but decreased to 2% during years 1 to 2: Further declines in AEs to 3% in years 2 to 3, 1% in years 3 to 4, and finally to 0 in years 4 to 5.

This same trend was observed for treatment discontinuation due to an AE; ibrutinib discontinuation was observed in 7%, 6%, 5%, 6%, and 1% of patients during year 0 to 1, 1 to 2, 2 to 3, 3 to 4, and in year 4 to 5, respectively.

Fifty-eight percent of patients remain on continuous ibrutinib treatment; duration of the BTK inhibitor was more than 3 years for 73% of patients, 4 years for 65%, and 27% of patients had >5 years of ibrutinib therapy. Overall, ibrutinib was discontinued by 29 (21%) patients due to an AE.

“The rates of ibrutinib discontinuation due to disease progression were low and these patients responded to subsequent treatments,” Tedeschi noted. Twenty-one patients on ibrutinib had disease progression during follow-up, which included patients who had discontinued treatment. Only 8 (6%) patients experienced disease progression while actively on ibrutinib treatment.

Of the 21 patients discontinuing treatment due to an AE and the 8 discontinuing due to progressive disease (PD), the median time on study following discontinuation was 21 and 20 months, respectively. The median OS in the respective patients was not estimated and 20 months. Three patients with PD each received subsequent treatment with standard chemoimmunotherapy or novel agents. The best overall response reported for 9 of 14 patients included 7 responses, and 1 patient each had stable disease and PD.

“These findings represent the longest follow-up to date from a phase III study of first-line BTK-directed therapy,” Tadeschi noted. “Single-agent ibrutinib demonstrated PFS and OS benefit that was sustained over 5 years, including in patients with high-risk genomic features,”.

Tedeschi A, Burger J, Barr PM, et al. Five-year follow-up of patients receiving ibrutinib for first-line treatment of chronic lymphocytic leukemia. Presented at: 2019 European Hematology Association Congress; June 13-16, 2019; Amsterdam, Netherlands. Abstract S107.

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