Rule S, et al. ASH 2017:151

Median 3.5-year follow-up of ibrutinib treatment in patients with relapsed/refractory mantle cell lymphoma: A pooled analysis

Background

In relapsed/refractory (R/R) mantle cell lymphoma (MCL), time to next therapy generally decreases with each subsequent line of therapy. There is a need for treatments with higher durability of response and longer progression-free survival (PFS) to improve outcomes. Ibrutinib has previously been shown to improve PFS compared to temsirolimus in patients with R/R MCL.1 At the 2017 ASH Annual Meeting, mature follow-up of a large cohort of patients treated with ibrutinib across three studies was presented, with a median follow-up of 3.5 years.2

Study design

  • Patients were enrolled in one of three studies (PCYC-1104, SPARK, or RAY) between 2011 and 2013.
  • Ibrutinib 560 mg once daily was given orally until progressive disease or unacceptable toxicity.
  • Patients continuing to benefit from ibrutinib at the end of the studies could enrol in CAN3001, a phase IIIb, open-label access study.
    • In this study, safety reporting was limited to grade 3/4 adverse events (AEs) and serious AEs.
  • Efficacy outcomes included investigator-assessed tumour response, PFS, and overall survival (OS).
    • Cheson 2007 criteria3 were used, and all complete responses (CRs) were confirmed by positron emission tomography (plus bone marrow biopsy and/or endoscopy if positive at baseline).
  • Multivariate analysis was conducted to assess the effect of baseline characteristics on PFS and OS.

Key findings

Baseline characteristics and disposition

  • A total of 370 patients were included in the pooled analysis.
  • Median age was 67.5 years (range: 35–85).
  • The majority of patients were male (78.1%) with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–1 (93.5%).
  • Bulky disease (≥5 cm) occurred in 48.9% of patients, and 11.9% of patients had the blastoid variant of MCL.
  • Median duration of follow-up was 41.1 months (range: 0.2–72.1).
  • Eighty-seven patients (23.5%) rolled over to the CAN3001 study.
  • Treatment discontinuation occurred in 316 patients (85.4%).
    • Reasons for discontinuation included AE (n = 37), disease progression (n = 218), death (n = 19), alternative access to ibrutinib (n = 1), physician decision (n = 14), withdrawal of consent (n = 24), and other reasons (n = 3).
  • Approximately one-third of patients (n = 115; 31.1%) were treated with ibrutinib for ≥2 years.
  • Fifty-four patients remained on ibrutinib at the time of analysis, with a median exposure of 46.3 months (range: 28.8–72.1).
  • Maximum treatment exposure was 72 months.

Efficacy

  • Median PFS was 33.6 months in patients with one prior line of therapy (95% CI: 19.4–42.1). (Figure 1)
    • In the pooled intent-to-treat (ITT) population, median PFS was 13.0 months (95% CI: 8.4–16.8).
  • Median OS was not reached in patients with one prior line of therapy, and was 22.5 months in patients with >1 prior line of therapy.
    • In the ITT population, median OS was 26.7 months (95% CI: 22.5–38.4).
  • Overall response rate (ORR) was 69.7% in the ITT population, with 26.5% achieving a CR and 43.2% achieving a partial response (PR).
    • In patients with one prior line of therapy, ORR was 77.8%, CR rate was 36.4%, and PR rate was 41.4%.
    • In patients with >1 prior line of therapy, ORR was 66.8%, CR rate was 22.9%, and PR rate was 43.9%.
  • Median PFS was 46.2 months (95% CI: 42.1–not estimable [NE]) in patients who achieved a CR and 14.3 months (95% CI: 10.4–17.5) in patients who achieved a PR.
  • Median OS was NE (95% CI: 59.9–NE) in patients who achieved a CR and 26.2 months (95% CI: 21.6–34.7) in patients who achieved a PR.
  • In patients achieving a CR, median duration of response (DOR) was 4.5 years. (Table 1)
  • Patients with one prior line of therapy had a DOR that was more than double that of patients with >1 prior line of therapy.
  • ECOG PS, simplified MCL International Prognostic Index risk, number of prior lines of therapy, presence of bulky disease, and blastoid history were independent predictors of PFS with ibrutinib. (Figure 2)

Figure 1. PFS and OS by prior line of therapy

Table 1. DOR by best response and line of therapy

Figure 2. Independent predictors of PFS with ibrutinib (multivariate analysis)

Safety

  • The most common grade ≥3 treatment-emergent AEs (TEAEs) occurring in ≥5% of patients (by ITT population, patients with one prior therapy, and patients with >1 prior lines of therapy, respectively) were as follows:
    • Neutropenia (17%, 7.1%, and 20.7%);
    • Thrombocytopenia (12.2%, 7.1%, and 14%);
    • Pneumonia (11.9%, 7.1%, and 13.7%);
    • Anemia (9.5%, 5.1%, and 11.1%);
    • Atrial fibrillation (5.9%, 5.1%, and 6.3%); and
    • Hypertension (5.1%, 6.1%, and 4.8%).
  • Generally, grade 3/4 AEs were less common in patients with one prior line of therapy.
  • Secondary malignancies occurred in 9.7% of patients and were predominantly nonmelanoma skin cancers.
  • New onset grade ≥3 TEAEs generally decreased after the first year of treatment. (Figure 3)
    • A similar trend was observed for atrial fibrillation and bleeding.
  • New onset grade ≥3 TEAEs were generally lower in patients with one vs. >1 prior line of therapy.
  • Patients with significant cardiac risk factors were enrolled in the studies, including:
    • Hypertension (n = 176);
    • Hyperlipidemia (n = 60);
    • Atrial fibrillation/abnormal heart rhythm (n = 53);
    • Diabetes (n = 48); and
    • Coronary artery disease (n = 31).
  • The majority of patients who entered the study with a history of atrial fibrillation or arrhythmia did not have a recurrence (70%; 37 of 53).
  • Less than 2% of the 370 patients treated with ibrutinib discontinued or had a dose reduction due to grade ≥3 bleeding or atrial fibrillation. (Table 2)
    • No patients discontinued ibrutinib due to grade ≥3 atrial fibrillation.

Figure 3. Grade ≥3 TEAEs over time and by line of therapy

Table 2. Management of ibrutinib in patients with bleeding or atrial fibrillation

Key conclusions

  • In this mature pooled data set of 370 patients with R/R MCL from three studies:
    • The median PFS was 33.6 months for patients with one prior line of therapy;
    • The median PFS was 46.2 months for patients who achieved a CR; and
    • The median DOR was 55 months for patients who achieved a CR.
  • Clinical risk factors and number of prior lines of therapy predicted PFS with ibrutinib.
  • New onset grade ≥3 AEs were most common in the first year, generally decreased over time, and were less common in patients with only one prior line of therapy.
    • Less than 2% of patients had to reduce ibrutinib dose or discontinue due to atrial fibrillation or bleeding.
    • Most patients with a history of atrial fibrillation did not have a recurrence (70%).

References: 1. Dreyling M, Jurczak W, Jerkeman M, et al. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study. Lancet 2016;387(10020):770–8. 2. Rule S, Dreyling M, Goy A, et al. Median 3.5-year follow-up of ibrutinib treatment in patients with relapsed/refractory mantle cell lymphoma: a pooled analysis. ASH Annual Meeting Abstracts 2017:151. 3. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25(5):579–86.