Ongoing Phase III Trial Evaluates Treatment Discontinuation Methods in Treatment-Naive CLL

Jennifer Woyach, MD

Jennifer Woyach, MD

The randomized phase III Alliance A041702 clinical trial evaluating the combination of ibrutinib (Imbruvica) plus obinutuzumab (Gazyva) with or without venetoclax (Venclexta) is ongoing for patients with treatment-naïve chronic lymphocytic leukemia (CLL) who are 70 years or older.

This ongoing trial is evaluating a novel response-adapted treatment discontinuation method. Patients will receive either standard obinutuzumab with indefinite ibrutinib or the standard obinutuzumab with 14 cycles of ibrutinib and venetoclax. Upon completion of treatment in the triplet arm, patients will undergo testing to determine if they have achieved a minimal residual disease (MRD)-negative complete response (CR). If they have, they can stop treatment. Otherwise, ibrutinib will be continued indefinitely.

The goal of the study is to determine whether the novel response-adapted method is the more optimal strategy for discontinuing treatment based on progression-free survival (PFS) between the immunotherapy combination and the triplet arm using strategy of response-adapted treatment discontinuation, the primary end point.

Secondary end points include comparison of bone marrow MRD-negative CR rates and depth of response, overall survival (OS) between the control and experimental treatment strategies, and 5-year PFS and OS for treatment strategies. Investigators will also determine the safety of the regimen and treatment strategy. The findings from this clinical trial have the potential to change the standard of care in this patient population.

To be included in this trial, patients must have no prior treatments or have been previously treated for autoimmune complications with either steroids or rituximab (Rituxan). Patients should have intermediate- to high-risk Rai stage, and ECOG performance status of 0, 1, or 2, an ANC count of 1000/mm³or greater, and platelet counts of 30,000/mm³or greater.

In an interview withTargeted Oncology, Jennifer Woyach, MD, associate professor at the Ohio State University Comprehensive Cancer Center in Columbus, discussed the rationale for evaluating a response-dependent treatment discontinuation strategy for older patients with previously untreated CLL. She highlighted the importance of determining an optimal discontinuation strategy in this patient population.

Targeted Oncology: What is the rationale for the Alliance A041702 trial?

Woyach:This trial is the successor to the Alliance A014202 study, which was the randomized study that was reported at the end of 2018 and showed for elderly patients with previously untreated CLL that targeted therapy with ibrutinib or ibrutinib plus rituximab was superior to bendamustine plus rituximab. This trial is trying to take that a step further to see if we can optimize our targeted treatment by potentially allowing a mechanism for therapy discontinuation that includes a BTK inhibitor, which is an  effective frontline therapy for CLL.

In this study, we are taking patients who are aged 70 or older with previously untreated CLL, and they will be randomized 1:1 to either ibrutinib plus obinutuzumab or ibrutinib plus obinutuzumab and venetoclax. In patients who are enrolled to ibrutinib plus obinutuzumab, they will have the standard 6 cycles of obinutuzumab and will be treated indefinitely with ibrutinib.

For those patients randomized to the triplet arm, they will have the standard obinutuzumab and will complete a total of 14 cycles with ibrutinib and venetoclax. At the end of that time, they will have a response evaluation, which will include CAT scans and a bone marrow biopsy, and patients who have an MRD-negative CR would discontinue all therapy. For those who do not, they will continue taking ibrutinib indefinitely. The primary outcome of this study will be to look at PFS between those 2 arms using that strategy of a response-adapted discontinuation.

Targeted Oncology: What impact would these results have on the treatment landscape if the trial is positive?

Woyach:There is a lot of interest right now in combining our most effective therapies to produce a time-limited regimen. If positive, this would make it a standard of care to use combinations of BCL2 inhibitors plus BTK inhibitors plus CD20 antibodies with plans for discontinuation. There are other studies that are using similar approaches of combining 2 or 3 drugs with either fixed durations where everybody stays or other methods of choosing how patients would stop therapy. That whole body of literature will tell us what the best [method of discontinuation] is and whether we should be using a response-adapted discontinuation [approach] or stopping everybody at a particular time period.

Targeted Oncology: What is the utility of MRD, and how is it evolving in this space?

Woyach:We used to always use time-limited therapy with chemoimmunotherapy, but then we moved to more BTK inhibitor-based therapies where patients receive therapy indefinitely because patients do not reach those MRD-negative CRs. Now with venetoclax, we know [when used] in combination with rituximab in the relapsed setting or in combination with obinutuzumab in the frontline setting, it [results in] high rates of MRD-negative CRs. The data that have been coming out with longer follow-up are showing that patients who obtain deeper remissions tend to have longer remission durations after stopping treatment.

Right now, it is not the standard of care to check for MRD status at the end of therapy. The current standard is to do your fixed-dose regimen and then stop entirely, but there is a lot of interest to see if we should be personalizing this approach for patients.

Targeted Oncology: What are your final thoughts on the treatment landscape currently for patients with CLL?

Woyach: