Longest Follow-Up Maintains Ibrutinib Benefit in CLL/SLL Across Treatment Settings

The longest follow-up for ibrutinib (Imbruvica) monotherapy to date maintained the benefit of the Bruton’s tyrosine kinase inhibitor for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) across settings.

Eight-year follow-up from the phase Ib/II PCYC-1102 trial showed high rates of overall survival and overall responses as well as long-term tolerability in both the treatment-naïve and relapsed or refractory settings.

“This report describes the longest follow-up to date for single-agent ibrutinib in the first-line and relapsed/refractory settings, providing valuable clinical data on the efficacy, durability, and safety profile. Sustained efficacy of single-agent ibrutinib was observed as first-line treatment and treatment for relapsed/refractory CLL/SLL, including for patients with high-risk genomic factors,” study authors, led by John C. Byrd, MD, wrote in the report published inClinical Cancer Research.

PCYC-1102 was an open-label, nonrandomized trial studying the use of ibrutinib monotherapy in patients with CLL/SLL in both the frontline and relapsed/refractory settings. Patients treated in the first line (n = 31) were at least 65 years old and those treated in the relapsed/refractory setting (n = 101) were at least 18 years old and had received at least 1 prior therapy including a purine analog. All those who completed at least 6 treatment cycles of ibrutinib without signs of progression were allowed to join the PCYC-1103 extension study.

Treatment was administered at either 420 or 820 mg/day in 28-day cycles. The cohort of treatment-naïve patients receiving 820 mg/day closed before accrual was complete due to the comparable efficacy seen in the relapsed/refractory groups between the 2 dose levels.

The study was primarily looking at adverse events (AEs) with ibrutinib and secondary outcome measures included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

Responses in the Frontline Setting

In the treatment-naïve cohort, the median age was 71 years (range, 65-84). The majority of patients (74%) had an ECOG performance status of 0, and the remainder had a score of 1. Forty-two percent of patients had deletion 13q (del[13q]), 26% had trisomy 12, 48% had unmutatedIGHV,and 13% had complex karyotype.

Patients were followed for a median of 87 months (range, 1-98), and the median duration of treatment was 75 months (range, 0.3-98). Twelve patients were still receiving ibrutinib at the time of study closure and went on to continue ibrutinib treatment outside of the trial. Treatment discontinuation was due to AEs in 26% and disease progression in 6%.

The ORR was 87% with complete responses (CRs) in 35%, partial responses (PRs) in 45%, and PRs with lymphocytosis in 6%. The median DOR was not reached (range, 0+ to 96+).

Both the median PFS and OS were not reached, but the estimated 7-year PFS rate was 83% and the estimated OS rate was 84%.

Responses in the Relapsed/Refractory Setting

The previously treated patients had a median age of 64 years (range, 37-82) and three-fourths of the group (78%) were male. More than half the patients (53%) had an ECOG performance status of 1 and only 4% had a score of 2. Thirty-four percent of patients had del(17p), 28% had del(11q), 78% had unmutatedIGHV,and 37% had complex karyotype. Patients had received a median of 4 prior therapies (range, 1-12).

Patients were followed for a median of 82 months (range, 0.7+ to 98) and the median duration of treatment was 39 months (range, 0.3-98). Sixteen patients were still receiving ibrutinib at the time of study closure and went on to continue ibrutinib treatment outside of the trial. Treatment discontinuation was due to AEs in 23% and disease progression in 38%. The median time to progression of CLL without Richter’s transformation was 38 months (n = 29; range, 1-88).

The ORR was 89% with CRs in 10%, PRs in 76%, and PRs with lymphocytosis in 3%. The median DOR was 57 months (range, 0+ to 96+). Rates of response were also consistently high across all chromosomal abnormalities.

The median PFS was 52 months (95% CI, 38-70) and at 7 years, the estimated PFS rate was 34%. The median PFS tended to be longer in patients who had received fewer prior therapies with a median of 66 months for those who had received only 1 or 2 previous treatments compared with 39 months for those who had received at least 4.

Byrd et al commented: “in patients treated for relapsed/refractory CLL/SLL, ibrutinib administration in earlier lines of therapy resulted in improved PFS outcomes, providing evidence for earlier introduction of ibrutinib treatment.”

In patients who had both complex karyotype and del(17p), the median PFS was 25 months (95% CI, 12-33) but for those with only complex karyotype, the median PFS was 88 months (95% CI, 14-not estimable [NE]).

The median OS was 92 months (95% CI, 66-NE) and the estimated 7-year OS rate was 55%. OS, like PFS, also tended to be longer for those who had received fewer prior therapies.

Overall Responses

Lymphocytosis was observed in 115 patients, including a majority of patients with chromosomal abnormalities, and OS rates were greater for patients with lymphocytosis than without at 71% and 60% at 2 years, respectively. The median time to lymphocytosis was 0.26 months.

The median OS after disease progression was significantly shorter for those who had Richter’s transformation compared to those who did not (median 4 vs 50 months, respectively).

Additionally, patients who were above 50 years had better median OS periods than those who were younger.

Sustained hematologic improvement was seen in patients who had baseline cytopenias across all treatment settings.

Safety Profile Across Settings

In terms of safety, as previously reported, the most frequent adverse events (AEs) of grade 3 or higher were hypertension (28%), pneumonia (24%), and neutropenia (18%). The onset of most AEs decreased over time, except for in the case of hypertension.

Fewer grade 3 or higher AEs were reported for patients treated in the first line compared with those treated in the relapsed/refractory setting (81% vs 90%), even though patients treated upfront typically had a longer time on ibrutinib therapy. Hypertension, diarrhea, and hyponatremia occurred more frequently in patients treated upfront, whereas pneumonia, neutropenia, thrombocytopenia, sepsis, and cellulitis were more frequently observed in those treated in later lines. Grade 3 or higher infections were also observed more frequently in the relapsed/refractory setting.

AEs of clinical interest for ibrutinib therapy were atrial fibrillation, thrombocytopenia, anemia, and arthralgia, but were observed in only up to 11% of patients.

Second malignancies were reported in a total of 33 patients, which included nonmelanoma skin cancers in 22.

Serious AEs were reported in 68% of patients treated in the frontline versus 78% treated in the relapsed/refractory setting. With frontline treatment, the most frequent serious AEs were pneumonia, atrial fibrillation, hypertension, and pyrexia compared with pneumonia, atrial fibrillation, cellulitis, sepsis, bacteremia, and febrile neutropenia in the relapsed/refractory group. None of these were new compared with previous reports.

AEs led to dose reduction in 13% of patients treated in the frontline and in 19% treated in later lines. Dose reductions were more common in year 6 and year 7 for the first line and relapsed/refractory settings, respectively.

AEs leading to discontinuation only occurred in the relapsed/refractory setting and were frequently due to sepsis, diarrhea, and subdural hematoma. Richter’s transformation also led to discontinuation in 2 patients.

Findings from the PCYC-1102 trial led to the accelerated approval for ibrutinib in treating patients with relapsed/refractory CLL.

Reference:

Byrd JC, Furman RR, Coutre S, et all, Ibrutinib Treatment for First-Line and Relapsed/Refractory Chronic Lymphocytic Leukemia: Final Analysis of the Pivotal Phase 1b/2 PCYC-1102 Study [published online March 24, 2020].Clin Cancer Res.doi: 10.1158/1078-0432.CCR-19-2856.