Anti-BCL2/CD20 Combination Therapy for Frontline CLL

Alan P. Skarbnik, MD: In terms of BCL2 inhibitors, venetoclax is the approved agent at the moment. In the initial trials with venetoclax as a monotherapy for patients with a relapsed disease with 17p deletion and PLCG2 mutation. Even as a monotherapy, BCL2 had significant activity there. The idea behind the use of venetoclax is to reinstate the ability of the CLL [chronic lymphocytic leukemia] cells to regrow apoptosis. BCL2 is an antiapoptoticmolecule, and by inhibiting that we allow the release of pro-apoptotic back into the cytosol of the cells. The efficacy signal seen in the phase 2 trials, the first venetoclax was combined with an anti-CD20 monoclonal antibody. In that case, the rituximab in the MURANO trial for relapse set disease compared with BR [bendamustine, rituximab], and it showed an improved PFS [progression-free survival] and overall survival in patients in that trial.

As the development of the drug was brought to the frontline setting the decision was made to combine it with obinutuzumab; another anti-CD20 molecule antibody. Obinutuzumab has been shown to improve in this trial to be superior to rituximab in CLL, particularly the CLL11 trial. Not only in terms of response but prolonged PFS and much higher rates of minimal residual disease negativity in those patients. The mechanism of action doesn’t cross. It is an antibody-dependent cell site of toxicity-driven monoclonal antibody. It also leads to some complement-dependent cytotoxicity and direct cell death. Rituximab does not drive that mechanism of action. It’s an interesting compound to combine with venetoclax, particularly in the frontline setting.

At the time that the frontline trial was designed, CLL14, the benchmark for comparison was chlorambucil and obinutuzumab, which was the benchmark developed from CLL11. Using the obinutuzumab in both arms certainly made sense. So, patients with untreated CLL were randomized to receive either chlorambucil for 12 months and obinutuzumab for 6 months vs obinutuzumab for 6 months and venetoclax for 12 months. The duration of therapy was the same, which is important because it gave a better benchmark for comparison, in terms of how long the disease was supposedly suppressed by a treatment. There were 432 enrolled patients through a randomized 1:1 and this included patients with high-risk disease IGHV-mutated disease. This year there was an update with the 39.6 months of follow-up presented at ASCO [American Society of Clinical Oncology annual meeting]. This study was first presented a year ago and then presented again this year with a longer follow-up. Progression-free survival was superior for venetoclax-obinutuzumab when compared with chlorambucil-obinutuzumab. That superiority was sustained in the updated data set. The median PFS for venetoclax-obinutuzumab was not reached, and the PFS for chlorambucil-obinutuzumab was 35.6 months with a very interesting hazard ratio of .31—a very statistically significant P value.

It’s estimated progression-free survival at 3 years in the venetoclax-obinutuzumab arm was 81.9% and the chlorambucil-obinutuzumab arm was 49.5%. This benefit was sustained across all subset group analyses, including high-risk disease, which was the question at the beginning. This improvement was also seen in the IGHV-mutated subset of patients. A previous study, iLLUMINATE, which used obinutuzumab with ibrutinib, compared with the same arm, chlorambucil vs obinutuzumab, didn’t show a superiority in the IGHV-mutated or lower-risk population. This was an interesting finding of the study, cementing the position of venetoclax-obinutuzumab as a solid choice for patients in the frontline setting. This includes patients with high-risk disease. However, for patients with high-risk disease, even though the PFS was superior when compared with chlorambucil-obinutuzumab, upon discontinuation, these were patients who would start seeing the progression happening a little sooner. It is still up for questioning whether the exploration treatment is appropriate for patients with high-risk disease. But taking the other side, for other patients, it is certainly a very good choice.

Transcript Edited for Clarity