Fixed-Duration Ibrutinib/Venetoclax Significantly Prolongs PFS Over SOC in CLL and Comorbidities

Arnon P. Kater, MD, PhD

The fixed-duration combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) produced deep responses and improved progression-free survival (PFS) vs chlorambucil plus obinutuzumab (Gazyva) when used in previously untreated patients with chronic lymphocytic leukemia (CLL) who were older and/or who had comorbidities, according to findings from the phase 3 GLOW trial (NCT03462719) published in the New England Journal of Medicine.¹

At a median follow-up of 27.7 months (range, 1.7-33.8), data showed that the median PFS was not yet reached (NR; 95% CI, 31.2-NR) with ibrutinib plus venetoclax vs 21.0 months (95% CI, 16.6-24.7) with chlorambucil plus obinutuzumab, per independent review committee (IRC) assessment (HR, 0.216; 95% CI, 0.131-0.357; P < .001). Investigator-assessed PFS was consistent with the IRC findings.

Moreover, the estimated 24-month PFS rates reported with ibrutinib/venetoclax and chlorambucil/obinutuzumab were 84.4% and 44.1%, respectively. At a median follow-up of 34.1 months, the estimated 30-month PFS rates were 80.5% and 35.8% in the investigative and control arms, respectively.

“Ibrutinib/venetoclax significantly enhanced PFS vs chlorambucil/obinutuzumab, and this benefit was consistent across prespecified subgroups, such as older patients and those with comorbidities, and stratification factors such as IGHV mutational status,” lead study author Arnon P. Kater, MD, PhD, professor of Internal Medicine at the University of Amsterdam's Faculty of Medicine in Amsterdam, Netherlands, and colleagues, wrote in the paper.

Chemoimmunotherapy has been established as first-line standard of care (SOC) for patients with CLL, with chlorambucil/obinutuzumab serving as a treatment option for elderly patients with comorbidities and without TP53 alterations. However, this regimen requires cumbersome infusions, and remission durations are suboptimal for many patients.²

Previously, data from the phase 2 CAPITIVATE trial (NCT02910583) demonstrated that ibrutinib plus venetoclax resulted in a 24-month PFS rate of 94% (95% CI, 88%-97%) and 97% (95% CI, 89%-99%) in patients CLL or small lymphocytic lymphoma (SLL) with high-risk features and patients without high-risk features, respectively.³

To participate on the GLOW trial, patients were required to be at least 65 years of age, or between the ages of 18 years and 64 years with a Cumulative Illness Rating Scale (CIRS) score greater than 6. Patients also needed to have active CLL or SLL that required treatment per International Workshop on Chronic Lymphocytic Leukemia criteria.

Key exclusion criteria included the presence of a 17p deletion or a TP53 mutation at enrollment, bleeding disorders, central nervous system involvement, Richter syndrome, or uncontrolled autoimmune hemolytic anemia or thrombocytopenia.

Study participants were randomized 1:1 to receive ibrutinib plus venetoclax or chlorambucil plus obinutuzumab. Those in the investigative arm were given 3 lead-in cycles consisting of 420 mg of oral ibrutinib once daily, followed by 12 cycles of the combination. Venetoclax was started in cycle 4 with dose ramp-up in accordance with the label over 5 weeks, ranging from daily doses of 20 mg, 50 mg, 100 mg, 200 mg, to 400 mg, and continued at 400 mg daily from cycle 5 onward. Ibrutinib and venetoclax were given as part of 28-day treatment cycles.

Patients in the control arm received 6 cycles of treatment consisting of 1000 mg of intravenous (IV) obinutuzumab daily on days 1 (or 100 mg on day 1 and 900 mg on day 2), 8, and 15 of cycle 1, then on day 1 of cycles 2 through 6, plus IV chlorambucil at 0.5 mg/kg on days 1 and 15 of each cycle.

PFS per IRC assessment served as the primary end point of the trial. Investigator-assessed PFS was also measured in a supplementary analysis. Secondary end points included best rates of undetectable minimal residual disease (MRD) in the bone marrow by next-generation sequencing, complete response (CR) rate, overall response rate (ORR), overall survival (OS), time to next treatment, and safety.

Among evaluable patients in the ibrutinib/venetoclax arm (n = 106) and the chlorambucil/obinutuzumab arm (n = 105), the median age was 71.0 years (range, 47-93) and 71.0 years (range, 57-88), respectively. Most patients were men (55.7% and 60.0%, respectively), had an ECOG performance status of 1 or 2 (67% and 62.9%), were Rai stage III or IV (57.3% and 52.5%), and had IGHV-unmutated disease (51.9% and 51.4%).

The median CIRS scores were 9 (range, 1-20) and 8 (range, 0-20) in the investigative and control arms, respectively. The median CrCL was 66.5 mL/min (range, 34.0-168.1) and 63.2 ml/min (range, 32.3-180.9). Bulky disease of at least 5 cm was observed in 39.0% and 36.2% of patients in the ibrutinib/venetoclax and chlorambucil/obinutuzumab arms, respectively. Moreover, 11q deletions were detected in 18.9% and 17.1% of patients, respectively, and TP53 mutations were detected after enrollment in 6.6% and 1.9% of patients.

Additional data showed that the best undetectable MRD rate was 55.7% in the ibrutinib/venetoclax arm vs 21.0% in the chlorambucil/obinutuzumab arm (P < .001). Three months after treatment completion, 51.9% of patients in the investigative arm had undetectable MRD vs 17.1% of those in the control arm. When measured in the peripheral blood, these rates were 54.7% and 39.0%, respectively. Additionally, sustained undetectable MRD in the peripheral blood from 3 months to 12 months following the end of treatment was observed in 84.5% and 29.3% of patients in the investigative and control arms, respectively.

The combination of ibrutinib plus venetoclax elicited an ORR of 86.8% which was similar to that of 84.8% with chlorambucil plus obinutuzumab arm. However, ibrutinib/venetoclax produced a significantly higher CR rate, including CR with incomplete bone marrow recovery, than that of chlorambucil/obinutuzumab, at 38.7% and 11.4%, respectively. The 24-month duration of response rate was 90% in the ibrutinib/venetoclax arm vs 41% in the chlorambucil/obinutuzumab arm.

At the time of the primary analysis, 11 deaths occurred in the ibrutinib/venetoclax arm vs 12 in the chlorambucil/obinutuzumab arm, with no significant difference in OS between the groups (HR, 1.048; 95% CI, 0.454-2.419). The most common causes of death between the arms included infections (n = 10), with 5 patients because of COVID-19, and cardiac events (n = 4). With the extended follow-up, 4 more deaths were reported, all in the control arm. In total, 11 patients died in the ibrutinib/venetoclax arm vs 16 in the chlorambucil/obinutuzumab arm (HR, 0.760; 95% CI, 0.352-1.642).

Diarrhea (50.9%) and neutropenia (41.5%) were the most common adverse effects (AEs) of any grade reported in the ibrutinib/venetoclax arm. The most common any-grade AEs experienced in the chlorambucil/obinutuzumab arm were neutropenia (58.1%) and infusion-related reactions (29.5%).

Grade 3 or higher AEs occurred in 75.5% and 69.5% of patients in the investigative and control arms, respectively. The most frequent grade 3/4 AEs included neutropenia (34.9% and 49.5% in the investigative and control arms, respectively), infections and infestations (15.1% and 10.5%), diarrhea (10.4% and 1.0%), hypertension (7.5% and 1.9%), atrial fibrillation (6.6% and 0%), and thrombocytopenia (5.7% and 20%).

Notably, 7 grade 5 AEs occurred in the ibrutinib/venetoclax arm, including infections and infestations (n = 2), sudden death (n = 2), cardiac failure (n = 1), sinus node disfunction (n = 1), ischemic stroke (n = 1), and malignant neoplasm (n = 1). In the chlorambucil/obinutuzumab arm, 1 patient experienced grade 5 cholestasis and 1 patient had grade 5 pneumonia.

Four of the treatment-emergent deaths in the ibrutinib/venetoclax arm group occurred during ibrutinib lead-in treatment. The 4 cardiac or sudden deaths in the ibrutinib/venetoclax arm occurred in patients with a CIRS score of at least 10 or an ECOG performance of 2 who had a history of hypertension, cardiovascular disease, and/or diabetes.

“Data from the GLOW trial, in which two-thirds of patients had preexisting hypertension, emphasize the importance of careful assessment of underlying cardiac risk factors when initiating treatment,” the study authors concluded. “The results further highlight the need for improved predictive markers for cardiac events among elderly patients and/or those with comorbidities undergoing CLL treatment.”

References

1. Kater AP, Owen C, Moreno C, et al. Fixed-duration ibrutinib-venetoclax in patients with chronic lymphocytic leukemia and comorbidities. N Engl J Med. Published online May 13, 2022. doi:10.1056/EVIDoa2200006
2. Eichhorst B, Robak T, Montserrat E, et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32(1):23-33. doi:10.1016/j.annonc.2020.09.019
3. Allan JN, Flinn IW, Siddiqi T, et al. Fixed-duration ibrutinib + venetoclax for first-line treatment of chronic lymphocytic leukemia in patients with high-risk features: phase 2 CAPTIVATE study. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Accessed April 11, 2022. Abstract CT028.