Venetoclax + Obinutuzumab: for Combination Therapy


Oncology clinical pharmacy specialist reviews the rationale for combining a BCL2 inhibitor with an anti-CD20 monoclonal antibody for the treatment of CLL.

Katie Culos, PharmD, BCOP: Venetoclax also was approved in the first-line setting. I am going to talk about the data that supported its approval. It was approved, as I talked about before, in combination with obinutuzumab. That decision was made because everybody was using that control arm as the way they were conducting and deigning their trials at the time. With ibrutinib and acalabrutinib, that’s how it was reviewed at first. We had seen that obinutuzumab was our preferred immunotherapy, and at the time of the trial design, venetoclax-obinutuzumab vs chlorambucil-obinutuzumab seemed like an equivalent comparison arm for that CLL14 trial.

When looking at the combination of these arms or the comparison, you’ve talked about it a few times, using fixed duration vs indefinite dosing is a huge difference. This might be a patient-preferred option. For some patients, as you said before, the thought of just getting through that 1 year and being done is something that will be their ticket to success. Potentially you have concerns about a patient’s ability to tolerate or comply with a long duration of an option. It’s also thought, as you alluded to earlier, that potentially a fixed duration could reduce resistance without continually exposing these malignant cells to your targeted agent.

Last September, there were follow-up data published in Lancet Oncology reporting a 2-year data after they had stopped that CLL14 trial. They had gotten their fixed duration of venetoclax-obinutuzumab or chlorambucil-obinutuzumab, and 24 months later patients were assessed, and we saw significantly longer progression-free survival [PFS] on the VEN [venetoclax] arm vs chlorambucil. We also saw that MRD [minimal residual disease] was higher with the venetoclax-treated group. Looking out at specific patient populations, high-risk patients with TP53 mutation, in this trial they saw that those treated with venetoclax and obinutuzumab had a progression-free survival at 3 years or around 70%. These data are great compared with what we had in previous regimens; however, it is going to be tougher to treat these high-risk patients than patients without a TP53 mutation.

Focusing on the dosing of venetoclax, I alluded to a dosing ramp-up. We know this agent is associated with a higher risk of tumor lysis syndrome in specifically CLL patients. There are several caveats that are important when you’re administering this patient, to prophylax for that. One is the dosing ramp-up. In this trial, CLL14, obinutuzumab was started, and they waited until day 22 to start the venetoclax. They used a 5-week ramp-up schedule starting at 20, 50, 100, 200 mg. Your target of 400 mg daily would, after 5 weeks and starting on day 22, put you at your target dose on day 1 of cycle 3 essentially.

Some other important things to note with venetoclax dosing is that you must be aware of drug interactions, especially those to CYP3A4 or P-glycoprotein. A close attention to concomitant medications is imperative to starting this treatment. Additionally, there are dosing adjustments provided if therapy is interrupted for toxicity. We do see a good amount of neutropenia in this patient population, which may warrant some interruptions of therapy. There are recommendations on what dose to jump back in when it the patient can start therapy again.

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