Ibrutinib/Venetoclax Triplet Demonstrates Frontline Activity in High-Risk CLL

The triplet regimen of ibrutinib (Imbruvica), venetoclax (Venclexta), and obinutuzumab (Gazyva) demonstrated encouraging response rates with an acceptable safety profile in treatment-naïve patients with high-risk chronic lymphocytic leukemia (CLL), according to results from the phase 2 CLL2GIVe trial that were presented during the 2020 European Hematology Association Congress.¹

Results showed that the triplet therapy led to a complete remission (CR) rate of 58.5% (95% CI, 42.1%-73.7%; P <.001), with a minimal residual disease (MRD) rate in the peripheral blood of 80.4% at cycle 15, showcasing efficacy as a frontline regimen for this patient population.

Prognosis for patients with high-risk CLL remains poor, investigators noted, and responses, including long-lasting remissions, to single-agent or combination therapy remain limited.

In May 2019, the FDA approved the combination of venetoclax and obinutuzumab for the frontline treatment of patients with CLL or small lymphocytic lymphoma. The approval was based on findings from the phase 3 CLL14 trial, in which the combination led to a 65% reduction in the risk of disease progression or death compared with obinutuzumab plus chlorambucil in this patient population (HR, 0.35; 95% CI, 0.23-0.53; P <.0001).^2,3

Moreover, in January 2019, the FDA approved the combination of ibrutinib and obinutuzumab as a first-line treatment for patients with CLL or small lymphocytic lymphoma, based on data from the phase 3 iLLUMINATE (PCYC-1130) trial. Here, ibrutinib/obinutuzumab led to a 77% reduction in the risk of disease progression or death versus chlorambucil/obinutuzumab (HR, 0.23; 95% CI, 0.15-0.37; P <.0001).⁴

The triplet regimen of ibrutinib, venetoclax, and obinutuzumab was previously explored in another phase 2 trial of patients with treatment-naïve and relapsed/refractory patients with CLL.⁵ At a median follow-up of 18 months, 23 of the 25 relapsed/refractory patients remained on study and achieved a response. There was 3 CRs, 3 patients achieved a CR with incomplete marrow recovery, and 17 had a partial response (PR). The overall response rate (ORR) for this population was 92% (95% CI, 74%-99%).

In the phase 2 CLL2GIVe trial, which was conducted by the German CLL study group, investigators evaluated the first-line triplet therapy of ibrutinib, venetoclax, and obinutuzumab in patients with high-risk CLL who harbored 17p deletions (del[17p]) or TP53 mutations.

All 3 agents were administered as part of a 6-month induction regimen. This was followed by a combination of venetoclax and ibrutinib for an additional 6 months. If undetectable MRD and CR, according to International Workshop CLL criteria, was not achieved, ibrutinib was administered as maintenance therapy for a total of 36 cycles.

Forty-one patients were enrolled, all of whom had adequate organ function, and 24 patients were male. The median age was 62 years (range, 35-85), and 78.0% of patients had a Binet stage of B or C; the median Cumulative Illness Rating Scale score was 3 (range, 0-8). Twenty-six patients had del(17p), 39 had TP53 mutations, and 32 patients had unmutated IGHV.

The primary end point was the CR rate at cycle 15, while secondary end points were safety parameters, MRD levels, progression-free survival, overall survival, and event-free survival.

At a median follow-up of 18.6 months (range, 3.6-36.5), all patients were included in the efficacy and safety analyses, and a final restaging was reached by 38 patients. Results also showed that the PR rate was 34.2% and 7.3% of responses were not available. In the 3 patients who were not assessable, 2 patients had died; 1 was due to an ovarian cancer diagnosis at cycle 3, and another was due to cardiac failure at cycle 9. The third patient withdrew consent at cycle 10. However, all 3 patients did achieve a PR as their best response.

Moreover, in 22 patients, the investigators noted that treatment was discontinued per protocol at cycle 15 due to undetectable MRD and CR/CR with incomplete hematologic recovery. Treatment was discontinued in 13 patients due to other reasons, such as adverse effects (AEs), patient decision, etc.

Regarding safety, the regimen was well tolerated. Grade 3 or higher AEs were reported as infections and infestations (19.5%), neutropenia (43.9%), infusion-related reaction (7.3%), headache (2.4%), thrombocytopenia (14.6%), arthralgia (2.4%), and atrial fibrillation (2.4%).

References

1. Huber H, Edenhofer S, Tresckow JV, et al. CLL2-GIVE, a prospective, open-label, multicenter phase-II trial of obinutuzumab (GA101, G), ibrutinib (I), plus venetoclax (VE) in untreated patients with CLL with 17p deletion / TP53 mutation. Presented at: 2020 European Hematology Association Congress; July 11 to 21, 2020; Virtual. Abstract S157.
2. Fischer K, Al-Sawaf O, Bahlo J, et al. Effect of fixed-duration venetoclax plus obinutuzumab (VenG) on progression-free survival (PFS), and rates and duration of minimal residual disease negativity (MRD—) in previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) and comorbidities. J Clin Oncol. 2019;37(suppl 15): 7502. doi:10.1200/JCO.2019.37.15_suppl.7502
3. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380:2095-2103. doi:10.1056/NEJMoa1900574
4. Moreno C, Greil R, Demirkan F, et al. Ibrutinib plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicenter, randomized, open-label, phase 3 trial. Lancet Oncol. 2019;20(1):43-56. doi:10.1016/S1470-2045(18)30788-5
5. Rogers KA, Huang Y, Ruppert AS, et al. Phase 2 study of combination obinutuzumab, ibrutinib, and venetoclax in treatment-naive and relapsed/refractory chronic lymphocytic leukemia. Blood. 2019;132(suppl 1):693. doi:10.1182/blood-2018-99-114169