Phase 1 Study of Venetoclax Combo Sets Stage for Future in Aggressive B-Cell Lymphomas

In an interview with Targeted Oncology, Sarah C. Rutherford, MD, discussed the phase 1 findings for the combination of venetoclax plus standard chemoimmunotherapy as treatment of patients with aggressive B-cell lymphomas.

A 600-mg dose of venetoclax on a 5-day treatment schedule has been selected as the recommend phase 2 dose for the treatment of patients with aggressive B-cell lymphomas, according to the results of a phase 1 study presented at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program.

Venetoclax (Venclexta) appears promising as treatment of patients with aggressive B-cell lymphomas in combination with standard chemoimmunotherapy, according to results of a phase 1 study presented at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program.

A 600-mg dose of venetoclax on a 5-day treatment schedule was selected as the recommended phase 2 dose in combination with dose-adjusted (DA) EPOCH-R, which was well tolerated in this patient population. The recommended dose will be used in the ongoing phase 2 study, which will further evaluate the effectiveness of this combination as treatment of patients with aggressive B-cell lymphomas.

This group of patients is known to have poor outcomes with standard-of-care treatments, and the combination is expected to improve outcomes. Although this was a phase 1 study, data were promising with 27 of the 30 patients achieving a complete response (CR) and 2 patients had a partial response. One patient was not evaluable. After a median follow-up of 13.5 months, 24 of the 27 patients remained in CR, 3 patients progressed after their response, and 2 patients died.

In an interview with Targeted Oncology, Sarah C. Rutherford, MD, lead author and assistant professor of medicine in the Division of Hematology/Oncology at Weill Cornell Medicine, discussed the findings for the combination of venetoclax plus standard chemoimmunotherapy as treatment of patients with aggressive B-cell lymphomas. She also highlighted the next steps, which include a phase 2 trial that is currently underway in this patient population.

TARGETED ONCOLOGY: What was the rationale for this study, and what is the unmet need in this patient population?

Rutherford: Aggressive B-cell lymphomas are often treated with the standard treatment, which is DA-EPOCH-R, a chemotherapy plus rituximab (Rituxan) and an immunotherapy drug. Some groups of patients still have poor outcomes, in particular the group of patients with double-hit lymphomas and double-expressor lymphomas. We studied a combination of DA-EPOCH-R with venetoclax, an oral BCL2 inhibitor. The study enrolled patients with multiple different types of aggressive B-cell lymphomas, but we are particularly looking forward to assessing this combination in patients with abnormal BCL2.

BCL2 is usually either rearranged or overexpressed in these aggressive lymphomas, so we think it is particularly compelling to combine venetoclax with DA-EPOCH-R. The study we have is a phase 1 in order to determine the maximum tolerated dose and recommended phase 2 dose of venetoclax in the combination with DA-EPOCH-R. There is a subsequent trial that is now ongoing that is looking at this combination in the double-hit and double-expressor lymphomas.

TARGETED ONCOLOGY: How frequently do you see patients with BCL2 abnormalities?

Rutherford: The actual double-hit lymphomas are somewhat rare, but they are a pretty prominent area of research. This study showed that 5% to 10% of diffuse large B-cell lymphomas are BCL2 rearranged. It is a relatively small population that has the double-hit lymphomas. There is a larger percentage, though, of maybe a third of patients who have BCL2 overexpression, or maybe even more than that. In our study, 21 of the 30 subjects had BCL2 overexpression, and that can happen in the context of having a BCL2rearrangement or not in that context, so it certainly affects a lot of patients.

TARGETED ONCOLOGY: What were the results from this study?

Rutherford: The objective was to determine the maximum tolerated dose and recommended phase 2 dose of venetoclax in combination with DA-EPOCH-R. There were secondary end points looking at the efficacy, and of course, we also looked at the safety, although this is a phase 1 trial. One of our key findings was that a 600-mg dose of venetoclax on a 5-day schedule was determined to be the dosing schedule we wanted to move forward with in subsequent phase 2 trials.

We found that the most common AEs were nausea, fatigue, and decreased blood counts, which are expected [adverse] effects for a DA-EPOCH-R backbone. The response rates were very promising. Again, this is a 30-subject trial, so we certainly need to look at these results with caution, but we look forward to the randomized trial of this combination that is ongoing. However, we did have an ORR of 97% and a CR rate of 93%, based on intention-to-treat analysis. Fifteen of our 30 subjects had double-hit lymphomas, which is a large portion of double-hit lymphomas, and 87% of those patients had a CR and 93% had a response of either a complete or partial response. We found that to be very promising.

TARGETED ONCOLOGY: Was there any element of the trial that surprised you?

Rutherford: I think the fact that we had so many double-hit lymphomas enrolling in the trial was surprising. I mentioned that this is relatively uncommon compared to other lymphomas, like diffuse large B-cell lymphoma and other subtypes, but we found there was a lot of interest in these patients. These patients are very motivated, and a lot of our patients here in New York in particular do research when they hear they have a diagnosis that is not as responsive to standard treatment. So I think the patients we had were seeking out clinical trials or getting referrals from other local oncology sites and others. I think that was exciting for us that we did have a high-risk population because when we look at the other disease characteristics, the median age of patients was about 64 years, which is representative of the patient population who tend to be older at diagnosis. Many of them have stage III or IV disease and a high International Prognostic Index score. There are often arguments that clinical trials are not representative of a standard patient population, but I would say that this group really was a high-risk patient population. I was very pleased that we found good outcomes and tolerability of the phase 2 dose of 600 mg on a 5-day schedule in that patient population.

TARGETED ONCOLOGY: What are the next steps for this research?

Rutherford: The next step is actually ongoing now. There is a clinical trial called Alliance 51701, which is a phase 2/3 study of venetoclax plus chemoimmunotherapy for double-hit, double-expressing lymphomas. The 2 high-risk groups that I mentioned, the double-hit lymphomas and double-expressor lymphomas, are being enrolled in this trial. They receive a chemotherapy backbone, which is the standard chemotherapy in double-hit lymphoma [of] DA-EPOCH-R that we used in our trial and the standard backbone in double-expressor lymphomas is R-CHOP. This trial randomizes patients to the appropriate backbone either with or without venetoclax. This is also using the dosing schedule we found tolerable in our trial.

Reference

Rutherford SC, Abramson JS, Bartlett NL, et al. Phase I study of the Bcl-2 inhibitor venetoclax with DA-EPOCH-R as initial therapy for aggressive B-cell lymphomas. J Clin Oncol. 2020;38(suppl):8003. doi:10.1200/JCO.2020.38.15_suppl.8003