Seymour JF, et al. ASH 2017:LBA-2

Venetoclax plus rituximab is superior to BR in patients with R/R CLL —interim analysis of the phase III MURANO study

Background

In the relapsed/refractory (R/R) setting, patients with chronic lymphocytic leukemia (CLL) have suboptimal responses to conventional chemoimmunotherapy.1 In a phase Ib study, the combination of rituximab and the B-cell lymphoma 2 inhibitor venetoclax (VenR) demonstrated high complete response (CR) and minimal residual disease (MRD) negativity rates, as well as an acceptable safety profile.2 At the 2017 ASH Annual Meeting, investigators presented pre-planned interim results from the phase III MURANO study, which evaluated the potential for time-limited therapy with VenR to improve progression-free survival (PFS) in patients with R/R CLL.3

Study design

  • In the multicentre, open-label, randomized, phase III MURANO study, VenR was compared to the combination of bendamustine and rituximab (BR) in patients with R/R CLL (NCT02005471).
  • Inclusion criteria were age ≥18 years, 1–3 prior lines of therapy including at least one chemotherapy-containing regimen, and prior bendamustine treatment (only if duration of response was ≥24 months).
  • Patients were stratified by the presence of the deletion of chromosome 17 (del[17p]), responsiveness to prior therapy, and geographic region.
  • Responsiveness to prior therapy was divided into high-risk and low-risk CLL.
  • High-risk CLL was defined as any of the following features:
  • Del(17p);
  • No response to front-line chemotherapy-containing regimens;
  • Relapsed ≤12 months after chemotherapy; or
  • Relapsed ≤24 months after chemoimmunotherapy.
  • The primary endpoint was investigator (INV)-assessed PFS.
  • Key secondary endpoints included independent review committee (IRC)-assessed CR, overall response rate (ORR), overall survival (OS), PFS, and MRD negativity in peripheral blood (PB).
  • MRD negativity was defined as <1 CLL cell per 10,000 leukocytes (10–4).
  • In both treatment arms, samples were collected at baseline, Day 1 of Cycle 4, at end of combination treatment, and every three months thereafter (or at response).
  • MRD was centrally assessed by allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) and/or multicolour flow cytometry.
  • MRD positivity by either ASO-PCR or flow cytometry was reported as MRD-positive.
  • Missing MRD data or assay failures were also reported as MRD-positive.
  • Key safety endpoints included serious adverse events (SAEs) and grade ≥3 adverse events (AEs).
  • The interim analysis included approximately 140 INV-assessed PFS events, which constituted 75% of the total information.

Study design

Key findings

Baseline characteristics and disposition

  • Patient demographics and disease characteristics were balanced between treatment arms.
  • The median age was 64.5 years in the VenR group and 66.0 years in the BR group.
  • Lymphocyte count at baseline was 43.1 × 109/L in the VenR group and 54.7 × 109/L in the BR group.
  • In both groups, del(17p) was present in 27% of patients and immunoglobulin heavy chain variable region (IGHV) was unmutated in 68% of patients.
  • Tumour protein 53 (TP53) was mutated in 25% and 28% of patients in the VenR and BR groups, respectively.
  • The majority of patients had received one prior therapy (57% and 60% in the VenR and BR groups, respectively), and the majority of prior therapies included an alkylating agent (93% and 95%, respectively), a purine analogue (81% in both groups), and an anti-CD20 (cluster of differentiation 20) antibody (78% and 76%, respectively).
  • In the VenR group 93% of patients received the full six treatment cycles.
  • Only 68% of the BR group received six treatment cycles.
  • Treatment discontinuation occurred in 25% of the VenR group (n = 48).
  • Reasons for discontinuation included disease progression (5%), AE without progression (12%), death (1%), and other (6%).
  • Treatment discontinuation occurred in 17% of the BR group (n = 34).
  • Reasons for discontinuation included disease progression (3%), AE without progression (6%), death (2%), and other (7%).
  • Richter’s transformation occurred in 3% of patients in both groups.

Efficacy

  • After a median follow-up of 23.8 months (range: 0.0–37.4), INV-assessed PFS was superior in the VenR group compared to BR (HR = 0.17, 95% CI: 0.11–0.25; p <0.0001). (Figure 1)
  • This superiority was consistent against all analyzed subgroups, including TP53 mutational status and baseline IGHV mutational status.
  • IRC-assessed PFS also demonstrated superiority of VenR over BR (HR = 0.19, 95% CI: 0.13–0.28; p <0.0001).
  • INV-assessed PFS was superior in the VenR group over BR regardless of del(17p) status:
  • Del(17p) present: HR = 0.13 (95% CI: 0.05–0.29); and
  • Del(17p) absent: HR = 0.19 (95% CI: 0.12–0.32).
  • INV and IRC-assessed ORRs were significantly improved in the VenR group. (Figure 2)
  • INV-assessed CR rates were also significantly higher in the VenR group.
  • Patients in the VenR group had higher rates of MRD negativity than the BR group at all measured time points. (Figure 3)
  • A significant and clinically meaningful increase in OS was observed in the VenR group (HR = 0.48, 95% CI: 0.25–0.90; p = 0.0186). (Figure 4)

Figure 1. Investigator-assessed PFS

Figure 2. Response rates

Figure 3. Peripheral blood MRD negativity rates

Figure 4. Overall survival

Safety

  • The AE reporting period was longer for the VenR group than for the BR group:
  • VenR group: Up to 28 days after the end of venetoclax treatment (maximum two years); and
  • BR group: Up to 90 days after the end of bendamustine treatment (maximum six months).
  • All patients in the VenR group and 98% of patients in the BR group experienced at least one AE.
  • SAEs occurred in 46% of the VenR group and 43% of the BR group.
  • Grade 3/4 AEs occurred in 82% of the VenR group and 70% of the BR group.
  • Grade 3/4 AEs that had a ≥2% difference in incidence between treatment arms are reported in Table 1.
  • Grade 5 AEs occurred in 5% of the VenR group and 6% of the BR group.
  • Causes of grade 5 AEs in the VenR group were pneumonia (n = 3, two of which were in the setting of progressive disease/Richter’s transformation, and one of which was with thrombocytopenia), sepsis (n = 1), cardiac failure (n = 1), myocardial infarction (n = 1), sudden cardiac death (n = 1), colorectal cancer (n = 1), status epilepticus (n = 1), and acute respiratory failure (n = 1).
  • Causes of grade 5 AEs in the BR arm included sepsis (n = 2), lung cancer (n = 2), Listeria sepsis (n = 1), Scedosporium infection (n = 1), lymphoma (n = 1), hemorrhagic stroke (n = 1), pulmonary embolism (n = 1), acute myeloid leukemia (n = 1), and sudden death (n = 1).

Table 1. Grade 3/4 AEs with ≥2% difference in incidence between arms

Key conclusions

  • In the MURANO study, VenR demonstrated:
  • Prolonged PFS compared to BR in patients with R/R CLL, which was consistent across subgroups and occurred regardless of del(17p) status;
  • Superior ORR and rate of peripheral blood MRD negativity that was maintained over time; and
  • A clinically meaningful improvement in OS compared to BR.
  • The safety profile observed in this study was consistent with previous reports for patients with R/R CLL.
  • VenR should be considered as a standard therapeutic option for this patient population.

References 1. Tam CS, Stilgenbauer S. How best to manage patients with chronic lymphocytic leukemia with 17p deletion and/or TP53 mutation? Leuk Lymphoma 2015;56(3):587–93. 2. Seymour JF, Ma S, Brander DM, et al. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study. Lancet Oncol 2017;18(2):230–40. 3. Seymour JF, Kipps T, Eichhorst B, et al. Venetoclax plus rituximab is superior to bendamustine plus rituximab in patients with relapsed/refractory chronic lymphocytic leukemia — results from pre-planned interim analysis of the randomized phase 3 MURANO study. ASH Annual Meeting Abstracts 2017:LBA-2.