Chemoimmunotherapy (CIT) is the standard of care for patients with treatment-naïve (TN) chronic lymphocytic leukemia (CLL). Ibrutinib (ibr), a first-in-class, once-daily inhibitor of Bruton’s tyrosine kinase, is approved in the United States and the European Union for the treatment of CLL and allows for treatment without chemotherapy.1,2 In the primary analysis of the phase 3 RESONATE-2 (PCYC-1115) study of single-agent ibr versus chlorambucil (Clb) in TN patients with CLL aged ≥65 years, ibr resulted in significantly longer progression-free survival (PFS) with 84% reduction in risk for progression or death and longer overall survival (OS) compared with Clb.2 At ASH 2017, the authors presented the results of a cross-trial comparison of ibr data, with additional follow-up of RESONATE-2 with phase 3 data of CIT regimens in the setting of TN CLL.3
The authors performed a cross-trial comparison between single-agent ibr therapy in RESONATE-2 (median follow-up, 35.7 months) and CIT regimens from published phase 3 studies conducted in patients with TN CLL: fludarabine + cyclophosphamide + rituximab (FCR) from CLL8 (FCR-CLL8),4 bendamustine + rituximab (BR) and FCR from CLL10 (FCR-CLL10),5 obinutuzumab + Clb (G-Clb) and R-Clb from CLL11,6 and ofatumumab + Clb (Ofa-Clb) from COMPLEMENT-1.7 Patients with del(17p) were excluded in RESONATE-2 and CLL10. RESONATE-2 enrolled patients aged ≥65 years.
The results showed treatment with single-agent ibr was associated with longer PFS compared with CIT regimens. Notably, PFS with ibr compared favorably with CIT studies that also excluded patients with del(17p) (BR and FCR-CLL10), and with CIT studies that enrolled older patients with comorbidities (G-Clb, R-Clb, and Ofa-Clb). Based on comparisons of hazard ratios (HRs) for PFS by baseline subgroups from studies that included Clb as the control arm, the magnitude of PFS benefit with ibr versus Clb in high-risk patients, including those with unmutated IGHV or del(11q), was greater than that observed with G-Clb or R-Clb versus Clb from CLL11. In patients with unmutated IGHV, the PFS HR (95% confidence interval [CI]) versus Clb was 0.08 (0.04-0.17) for ibr, 0.23 (0.16-0.34) for G-Clb, and 0.54 (0.38-0.76) for R-Clb. In patients with del(11q), the PFS HR (95% CI) versus Clb was 0.02 (0.005-0.11), 0.37 (0.17-0.81), and 0.99 (0.49-2.03) for ibr, G-Clb, and R-Clb, respectively.
In studies with older or less fit patients, OS with single-agent ibr appeared favorable to CIT. The overall rate of grade ≥3 adverse events (AEs) for CIT regimens was highest with FCR, followed by BR and Clb-based regimens. The rate of grade ≥3 AEs was similar for ibr and G-Clb. The rate of grade ≥3 infections varied by study and ranged from 9% with Ofa-Clb to 40% with FCR-CLL10, and was 25% with ibr. Rates of grade ≥3 cytopenias were generally lower with ibr compared with CIT, including neutropenia (ibr, 12%; CIT regimens, 26%-84%).
The authors concluded that, compared with published data of CIT regimens in patients with TN CLL, single-agent ibr was associated with longer PFS and a generally more favorable safety profile despite the longer treatment duration and much longer AE collection period. Acknowledging that interpretation of these results is limited by differences in study design and patient populations, and that conclusions cannot be made on whether ibr is superior to FCR, this cross-trial comparison suggests that ibr may eliminate the need for chemotherapy in some patients with TN CLL.
1. Pharmacyclics. 2017. www.imbruvicahcp.com.
2. Burger JA, et al. N Engl J Med. 2015;373:2425-2437.
3. Robak T, et al. ASH 2017. Abstract 1750.
4. Hallek M, et al. Lancet. 2010;376:1164-1174.
5. Eichhorst B, et al. Lancet Oncol. 2016;17:928-942.
6. Goede V, et al. N Engl J Med. 2014;370:1101-1110.
7. Hillmen P, et al. Lancet. 2015;385:1873-1883.