Study Protocol Differences May Affect BTK Inhibitor Performance in R/R CLL

Paolo Ghia, MD, PhD

Patients with relapsed/refractory chronic lymphocytic leukemia (CLL) treated with ibrutinib (Imbruvica) in the phase 3 RESONATE trial (NCT01578707) achieved a significantly longer median progression-free survival (PFS) compared with those in the phase 3 ALPINE trial (NCT03734016), as well as a higher yet nonsignificant 2-year PFS estimate vs those in the phase 3 ELEVATE-RR trial (NCT02477696), according to findings from a matching-adjusted indirect comparison (MAIC) study that were presented at the 17th Annual International Conference on Malignant Lymphoma.

“Ibrutinib PFS outcomes were consistent between RESONATE and ELEVATE-RR; however, significant differences in the performance of ibrutinib within ALPINE were identified,” lead study author Paolo Ghia, MD, PhD, of the Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, both in Milan Italy, and coauthors, wrote in a poster of the data.

The efficacy and safety of ibrutinib monotherapy vs ofatumumab (Kesimpta), zanubrutinib (Brukinsa), and acalabrutinib (Calquence) monotherapy in patients with relapsed/refractory CLL has been investigated in the randomized, open-label RESONATE, ALPINE, and ELEVATE-RR trials, respectively. In ELEVATE-RR, patients were also required to have a confirmed 17p deletion or 11q deletion mutation. However, the efficacy of ibrutinib has not been compared between the 3 trials.

In this analysis, individual patient data from the ibrutinib arm of RESONATE were separately adjusted to the ibrutinib arms of ALPINE and ELEVATE-RR using MAIC methodology. The baseline characteristics used in this study were age 75 years or older, bulky disease, a history of at least 3 (ALPINE) or at least 4 (ELEVATE-RR) prior treatments, beta-2 microglobulin levels over 3.5 mg/L, 11q deletion, and 17p deletion. Patient data from RESONATE with missing values for the baseline characteristics were excluded. When comparing patient data from RESONATE with those from ELEVATE-RR, the investigators included only patients from RESONATE with 17p or 11q deletions.

Upon matching the ibrutinib-treated populations between the 3 trials, the investigators compared adjusted overall response rate (ORR) and PFS data from RESONATE with those from ALPINE and ELEVATE-RR. For all 3 studies, ORR was defined as complete response (CR) plus CR with incomplete cell count recovery, nodular partial response (PR), and PR; PR with lymphocytosis and overall response with lymphocytosis were excluded from this ORR assessment.

This analysis included 785 total patients from RESONATE (n = 195), ALPINE (n = 325), and ELEVATE-RR (n = 265). After adjusting for patients with missing baseline characteristic data, 95 and 69 patients from RESONATE were compared with patients from ALPINE and ELEVATE-RR, respectively.

In the overall RESONATE ibrutinib-treated population, 22.1% of patients were at least 75 years of age, 63.6% of patients had bulky disease, 52.8% of patients had at least 3 prior treatments, and 52.8% of patients had at least 4 prior treatments. Additionally, 78.5%, 32.3%, and 32.3% of patients had beta-2 microglobulin levels over 3.5 mg/L, 11q deletions, and 17p deletions, respectively.

When unadjusted for comparison against the ALPINE ibrutinib-treated population, 21.8% of evaluable patients in the RESONATE ibrutinib arm (n = 179) were at least 75 years of age, and 63.7%, 52.5%, 83.8%, 34.1%, and 31.3% of patients had bulky disease, at least 3 prior treatments, beta-2 microglobulin levels over 3.5 mg/L, 11q deletions, and 17p deletions, respectively. When adjusted for comparison against the ALPINE ibrutinib-treated population, 21.2% of patients in the RESONATE ibrutinib arm were at least 75 years of age, and 45.8%, 20.9%, 66.5%, 27.2%, and 15.4% of patients had bulky disease, at least 3 prior treatments, beta-2 microglobulin levels over 3.5 mg/L, 11q deletions, and 17p deletions, respectively. In ALPINE, 21.2% of patients in the ibrutinib arm were at least 75 years of age, and 45.8%, 20.9%, 66.5%, 27.2%, and 15.4% of patients had bulky disease, at least 3 prior treatments, beta-2 microglobulin levels over 3.5 mg/L, 11q deletions, and 17p deletions, respectively.

When unadjusted for comparison against the ELEVATE-RR ibrutinib-treated population, 18.9% of evaluable patients in the RESONATE ibrutinib arm (n = 106) were at least 75 years of age, and 69.8%, 36.8%, 85.8%, 57.5%, and 52.8% of patients had bulky disease, at least 4 prior treatments, beta-2 microglobulin levels over 3.5 mg/L, 11q deletions, and 17p deletions, respectively. When adjusted for comparison against the ELEVATE-RR ibrutinib-treated population, 16.2% of patients in the RESONATE ibrutinib arm were at least 75 years of age, and 51.3%, 10.6%, 80.8%, 66.0%, and 45.3% of patients had bulky disease, at least 4 prior treatments, beta-2 microglobulin levels over 3.5 mg/L, 11q deletions, and 17p deletions, respectively. In ELEVATE-RR, 16.2% of patients in the ibrutinib arm were at least 75 years of age, and 51.3%, 10.6%, 80.8%, 66.0%, and 45.3% of patients had bulky disease, at least 4 prior treatments, beta-2 microglobulin levels over 3.5 mg/L, 11q deletions, and 17p deletions, respectively.

The adjusted median follow-up times in RESONATE were 36.0 months vs 29.6 months in ALPINE and 36.1 months vs 40.9 months in ELEVATE-RR.

Across both comparisons, the 2-year ORR estimates significantly favored the adjusted RESONATE data over both the ALPINE and ELEVATE-RR data. Compared with ALPINE, the adjusted RESONATE 2-year ORR estimate was 90% (95% CI, 86%-94%) vs 74% (95% CI, 69%-79%), translating to a 16% absolute difference (95% CI, 9%-22%; P < .0001). Compared with ELEVATE-RR, the adjusted RESONATE 2-year ORR estimate was 89% (95% CI, 83%-95%) vs 80% (95% CI, 75%-85%), translating to a 9% absolute difference (95% CI, 1%-17%; P = .038).

The 2-year PFS estimates in the adjusted RESONATE population were significantly higher than the corresponding ALPINE 2-year PFS estimates at 81% (95% CI, 74%-90%) vs 66% (95% CI, 60%-71%), respectively (P = .0112). The median PFS in the adjusted RESONATE population was 40.7 months vs 34.2 months in ALPINE (HR, 0.57; 95% CI, 0.39-0.84; P = .0048).

Though not a statistically significant difference, the 2-year PFS estimates in the adjusted RESONATE population were greater than the corresponding values in ELEVATE-RR, at 79% (95% CI, 69%-89%) vs 69% (95% CI, 64%-75%), respectively (P = .51). The median PFS in the adjusted RESONATE population was 41.2 months vs 44.1 months in ELEVATE-RR (HR, 0.85; 95% CI, 0.55-1.31; P = .46).

“Taking into consideration the inherent limitations of indirect comparisons, these results highlight the need for careful consideration of elements of protocol design, center selection, or treatment management that may lead to a significant impact on BTK inhibitor performance in clinical studies,” the study authors concluded.

Reference

Ghia P, Munir T, Burger JA, et al. Ibrutinib for treatment of relapsed/refractory chronic lymphocytic leukemia: a matching-adjusted indirect comparison of 3 randomized phase 3 trials. Presented at: 17th International Conference on Malignant Lymphoma; June 13-17, 2023. Lugano, Switzerland. Abstract 342.