Single-Agent Ibrutinib Promising in MCL and CLL, Improves Patient Well-Being

Three studies presented at the 59th Annual Meeting and Exposition of the American Society of Hematology (ASH) shared progress on the oral Bruton’s tyrosine kinase inhibitor, ibrutinib (Imbruvica), in the treatment of relapsed/refractory mantle cell lymphoma (MCL) and as a single agent in chronic lymphocytic leukemia (CLL).

The MCL results were the results of a 3.5-year follow-up of a pooled analysis of 370 patients with relapsed/refractory MCL who were treated with ibrutinib as part of 3 open-label studies: SPARK, RAY, and PCYC-1104. This longer-term follow-up, which included additional exposure to treatment, was conducted in 87 patients across the 3 studies who enrolled in the long-term access study, CAN3001, a phase 3b open-label study.¹

Patients received 560-mg ibrutinib orally, once daily, until progressive disease or unacceptable toxicity. Patients in the SPARK study were required to have received both rituximab

(Rituxan) and bortezomib (Velcade), while those in the RAY study had to have prior treatment with rituximab. Only those patients who continued to benefit from ibrutinib therapy at end

of the study could enroll in CAN3001. Crossover patients were excluded from the final pooled analysis. The study evaluated investigator-assessed tumor response, progression-free survival (PFS), and overall survival (OS). The median duration of followup in the pooled data set was 41.1 months (95% CI, 37.3-42.5), and the median treatment exposure was 11.1 months (range, 0.03-72.1). Fifty-four of the 87 (62.1%) patients enrolled in CAN3001 remain on ibrutinib and had received at least 2 prior lines of treatment (LOT).

At the 41-month follow-up check, 26.5% patients had achieved complete response (CR). The median PFS was 13.0 months in the overall patient population, 33.6 months (range,

19.4-42.1) in patients with 1 prior LOT, and 46.2 months (range, 42.1-not estimable) in patients achieving a CR. The median OS was 26.7 months:

• 53% patients were alive at 2 years (95% CI, 0.47-0.58)

• 45% patients were alive at 3 years (95% CI, 0.39-0.50)

• 37% patients were alive at 5 years (95% CI, 0.25-0.49)

Grade 3 or greater treatment-emergent adverse events (TEAEs) occurred in 295 (79.7%) patients, with the new-onset events decreasing after the first year, the authors reported. The

most common grade ≥ 3 TEAEs were neutropenia (17.0%), thrombocytopenia (12.2%), pneumonia (11.9%), anemia (9.5%), atrial fibrillation (5.9%), and hypertension (5.1%)—a majority were more common during the first year of ibrutinib treatment. Treatment-emergent severe adverse events (SAEs) occurred in 229 (61.9%) patients, and new-onset SAEs decreased over time.

Another presentation at the meeting reported results from a crossover study that compared single-agent ibrutinib (RESONATE-2) and chemoimmunotherapy regimens in treatment-naïve patients with patients with CLL from published studies with the following regimens:²

• Fludarabine + cyclophosphamide + rituximab (FCR) from CLL8 (FCR-CLL8), published in The Lancet³

• Bendamustine + rituximab (BR) and FCR from CLL10 (FCRCLL10),published in Lancet Oncology⁴

• Obinutuzumab (Gazyva) + chlorambucil (G-Clb) and rituximab + Clb (R-Clb) from CLL11, published in the New England Journal of Medicine⁵

• Ofatumumab + Clb (Ofa-Clb) from COMPLEMENT-1, published in The Lancet⁶

Limitations of the current analysis, the authors write, were the lack of available patient-level data from the chemoimmunotherapy studies and differences in study design and patient

eligibility criteria.

The median age across the studies ranged from 61 to 74 years; older patients usually enrolled in studies with ibrutinib, G-Clb, or R-Clb. Median CIRS scores ranged from 1 to 9, with lower comorbidity scores for patients treated with BR, FCR-CLL10, and FCR-CLL8.

Treatment with single-agent ibrutinib, the authors report, was associated with longer PFS compared with chemoimmunotherapy regimens; particularly, PFS with ibrutinib compared favorably to chemoimmunotherapy studies that also excluded patients with del(17p) (BR and FCR-CLL10) and those that enrolled older patients with comorbidities (G-Clb, R-Clb, and Ofa-Clb). In patients with unmutated IGHV, the PFS hazard ratio (HR) compared with chlorambucil was 0.08 (95% CI, 0.04-0.17) for ibrutinib, 0.23 (95% CI, 0.16-0.34) for G-Clb, and 0.54 (95% CI, 0.38-0.76) for R-Clb. In patients with del(11q), the PFS HR compared with chlorambucil was 0.02 (95% CI, 0.005-0.11), 0.37 (95% CI, 0.17-0.81), and 0.99 (0.49-2.03) for ibrutinib, G-Clb, and R-Clb, respectively. PFS rates across baseline groups were favorable with ibrutinib, compared with BR or FCR regimens in CLL10, especially in patients who had advanced disease, bulky lymph nodes, unmutated IGHV, and del(11q).

OS with single-agent ibrutinib favored chemoimmunotherapy in studies with older or less fit patients; however, compared with chlorambucil, OS with ibrutinib alone was better relative to Ofa-Clb, R-Clb, and G-Clb. The overall rate of grade ≥3 adverse events (AEs) for chemoimmunotherapy regimens was highest with FCR, followed by BR and chlorambucil-based

regimens; the rate was similar for ibrutinib and G-Clb despite the longer data collection period for ibrutinib. The rate of grade ≥3 infections varied by study and ranged from 9% with Ofa-Clb to 25% with ibrutinib to 40% with FCR-CLL10. Rates of grade ≥3 cytopenias were generally lower with ibrutinib compared with chemoimmunotherapy.

Despite its limitations, the authors propose that the results of their cross-trial comparison suggest that ibrutinib may potentially eliminate the need for chemotherapy in some patients with treatmentnaïve CLL.

Quality-of-life observations from the phase 3 RESONATE-2 study—conducted in older, treatment-naïve patients with CLL or small lymphocytic leukemia—were also presented at the

ASH meeting.⁷ With respect to clinical outcomes, single-agent ibrutinib in this patient population reduced the risk of disease progression or death by 84%, compared with chlorambucil, at a median follow-up of 18.4 months.

Patients 65 years or older were randomized to receive 420-mg ibrutinib once daily until progressive disease or chlorambucil for up to 12 months. Patients who progressed on chlorambucil had the option of receiving second-line ibrutinib. The various patient-reported outcomes (PROs) that were measured included FACIT (Functional Assessment

of Chronic Illness Therapy)-Fatigue, EQ-5D-5L, Q-TWiST, and EORTC QLQ-C30 global health status. Q-TWiST, and EORTC QLQ-C30 global health status.

The median follow-up among 269 patients, who had initiated therapy due to progressive marrow failure (38%), lymphadenopathy (37%), splenomegaly (30%), fatigue (27%), or night sweats (25%), was 35.7 months with ibrutinib and 34.4 months with chlorambucil. Ibrutinib treatment resulted in significantly longer PFS compared with chlorambucil (median, not reached vs 15.0 months).

Additionally, there was an 87% reduction in risk of progression or death with ibrutinib (HR, 0.130; 95% CI, 0.081-0.208). Importantly, for this particular study, the authors report greater and sustained improvements in PROs, which improved over time:

• FACIT-F (P = .0021) and EQ-5D-5L Visual Analogue Scale (P = .0004) by repeated measures. Crossover patients from the chlorambucil arm saw improved PROs.

• Approximately 87% of patients on ibrutinib (vs 52% on chlorambucil) had decreased/normalized lymphadenopathy within 2 months; this effect was sustained through 36 months.

• Disease symptoms, including fatigue and night sweats, improved more frequently with ibrutinib compared with chlorambucil. Sustained hematologic improvement was observed with

ibrutinib for hemoglobin (90% vs 45%; P <.0001) and platelets (83% vs 46%; P = .0032) among patients who had baseline cytopenia.

• Medical resource utilization burden was less with ibrutinib in the first year (use of intravenous immunoglobulin, growth factors, or transfusions) and continued to decrease.

• During the first year of treatment, patients on ibrutinib presented with less grade ≥3 neutropenia (8% and 18%) and anemia (6% and 8%) compared with chlorambucil.

• Other common grade ≥3 AEs were pneumonia (5% and 2%) and hypertension (4% and 0%).

Based on their Q-TWiST analysis at a median followup of 18.4 months, the authors report that the mean time spent without symptoms of disease progression or grade 3-4 treatment toxicity was longer with ibrutinib (501 vs 351 days; 95% CI, 109, 193). References

1. 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. In: Proceedings from the 59th Annual Meeting and Exposition of the American Society of Hematology; December 9-12, 2017; Atlanta, GA. Abstract 151. ash.confex.com/ash/2017/webprogram/Paper107064.html.

2. Robak T, Burger JA, Tedeschi A, et al. Single-agent ibrutinib vs chemoimmunotherapy regimens for treatment-naïve patients with chronic lymphocytic leukemia (cll): a cross-trial comparison. In: Proceedings from the 59th Annual Meeting and Exposition of the American Society of Hematology; December 9-12, 2017; Atlanta, GA. Abstract 1750. ash.confex.com/ash/2017/webprogram/Paper101257.html.

3. Hallek M, Fischer K, Fingerle-Rowson G, et al; International group of investigators; German Chronic Lymphocytic Leukaemia Study Group. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376(9747):1164-1174. doi: 10.1016/S0140-6736(10)61381-5.

4. Eichhorst B, Fink AM2, Bahlo J, et al; International group of investigators; German CLL Study Group (GCLLSG). First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016;17(7):928-942. doi: 10.1016/S1470-2045(16)30051-1.

5. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12):1101-1110. doi: 10.1056/NEJMoa1313984.

6. Hillmen P, Robak T, Janssens A, et al; COMPLEMENT 1 Study Investigators. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet. 2015;385(9980):1873-1883. doi: 10.1016/S0140-6736(15)60027-7.

7. Tedeschi A, Owen C, Robak T, et al. Prolonged improvement in patientreported outcomes (pros) and well-being in older patients with treatmentnaïve (tn) chronic lymphocytic leukemia treated with ibrutinib (ibr): 3-year follow-up of the RESONATE-2 study. In: Proceedings from the 59th Annual Meeting and Exposition of the American Society of Hematology;

December 9-12, 2017; Atlanta, GA. Abstract 1746. ash.confex.com/ash/2017/webprogram/Paper101468.html.

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