Venetoclax Monotherapy Leads to Responses, Genomic Changes in R/R CLL

Jennifer A. Woyach, MD

Treatment with venetoclax (Venclexta) monotherapy elicited durable responses and a tolerable safety profile in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who were previously treated with a B-cell receptor (BCR) inhibitor, irrespective of BTK mutation status, and the loss of BTK mutations during treatment with venetoclax in a small proportion of patients could re-sensitize them to covalent BTK inhibitors, according to Jennifer A. Woyach, MD.

She also noted that acquired BCL-2 mutations observed in this study support further exploration of strategies utilizing time-limited venetoclax.

Woyach presented updated findings from a phase 2 trial (NCT02141282) at the 2023 International Workshop on CLL, which showed that patients with relapsed/refractory CLL who were treated with venetoclax after previously receiving ibrutinib (Imbruvica; arm A) or idelalisib (Zydelig; arm B) experienced an objective response rate (ORR) of 66%. Those in arm A (n = 91) achieved an ORR of 65%, and those in arm B (n = 36) had an ORR of 69%.

Furthermore, the median progression-free survival (PFS) for patients with prior ibrutinib treatment was 24.7 months (95% CI, 19.2-40.9), and those with prior idelalisib treatment had a median PFS of 43.4 months (95% CI, 20.1–not evaluable [NE]). The median PFS for all patients was 33.7 months (95% CI, 21.8-46.2). The median overall survival (OS) was 69.6 months (95% CI, 51.3-NE) for patients in arm A, not reached (NR; 95% CI, 57.2-NE) for those in arm B, and 70.6 months (95% CI, 62.2%-NE) for all patients.

Patients with preexisting BTK mutations (n = 34) achieved a median PFS of 21.9 months (95% CI, 13.6-36.9), and those without preexisting BTK mutations (n = 38) had a median PFS of 19.2 months (95% CI, 15.0-48.9). The ORRs were 79% (95% CI, 62%-91%) and 87% (95% CI, 71%-95%), respectively.

Notably, 5 of 33 evaluable patients lost BTK mutations during treatment with venetoclax. Furthermore, 19% of evaluable patients (n = 13/68) acquired BCL-2 mutations, including 8 patients who had multiple BCL-2 mutations.

“[These analyses] show the continued safety and efficacy of venetoclax monotherapy after treatment with a BCR receptor antagonist. Most patients will still have a BTK mutation if they had 1 prior to the study. As expected, we see the acquisition of mutations in BCL-2,” Woyach said in an interview with OncLive^®.

In the interview, Woyach elucidated the updated results generated from the phase 2 study of venetoclax monotherapy in patients with relapsed/refractory CLL whose disease progressed on a prior BCR inhibitor, expanded on key findings from a genomic analysis from the study, and highlighted what these findings could mean for the CLL treatment paradigm.

Woyach is a professor in the Division of Hematology at The Ohio State University, and coleader of the Leukemia Research Program at The Ohio State Comprehensive Cancer Center–James in Columbus.

OncLive: Could you expand on the rationale for exploring recurrent genomic alterations in patients with relapsed/refractory CLL treated with venetoclax monotherapy?

Woyach: This study starts with long-term follow-up from a phase 2 monotherapy study of venetoclax in patients who were previously treated with either ibrutinib or idelalisib. From this study, we presented long-term data, and we looked at some genomic data from patients from whom we had pretreatment samples [and samples] either at the time of progression or at a time of continuing response when they went off study.

Could expand on the key findings from this long-term efficacy analysis?

For the clinical follow-up on the trial, [data] looked fairly similar to what had previously been published. These 2 cohorts were published independently. There were 91 patients on the ibrutinib cohort and [36] patients in the idelalisib cohort. We looked at long-term outcomes, and we saw that [the median] PFS was 33.7 months [95% CI, 21.8-46.2] for the entire cohort [n = 127], and this was a little longer for patients who were previously treated with idelalisib [43.4 months]. It was a bit shorter [at 24.7 months] for those patients previously treated with ibrutinib. We didn’t see any new safety signals with this long-term analysis.

What were the key findings from the genomic analysis?

We looked at patients for genomic alterations in BTK, TP53, and BCL-2. Forty-seven percent of the total all patients [with preexisting BTK mutations] had BTK C481 mutations, and we didn’t see any difference in PFS on venetoclax for patients with or without those mutations. We did see longer OS for patients who did not have [preexisting] BTK mutations. Likely, that's reflective of the fact that those patients either weren't on ibrutinib at all and could still take a BTK inhibitor, or they were intolerant of the BTK inhibitor rather than resistant to it.

We saw that in the patients with the pre- and post-treatment samples available, almost all patients [n = 28/33] retained a BTK C481 mutation at the time of relapse, although we did see 5 patients where that mutation went away, perhaps indicating that you may be able to re-sensitize those patients to a covalent BTK inhibitor.

TP53 mutations were acquired in 4 patients in the total cohort at the time of disease progression. We looked at BCL-2 mutations and found them in 30% of patients at the time of progression [n = 9/30], and in 11% of patients at a time of continuing response [n = 4/38], meaning those who went off the study either for toxicity or went on to an extension trial of venetoclax. Looking at the BCL-2 mutations, in 5 patients, we found only 1 mutation in BCL-2, and 8 patients had more than 1 mutation in BCL-2.

In general, the allelic frequencies [of BCL-2 mutations] were subclonal [≤25%] in almost all patients. In patients who were still responding to venetoclax, we found very low allelic frequencies of these mutations, and generally, they were a little higher in the patients who had progression.

Regarding the results, how did they compare to what you hypothesized at the launch of the trial?

The study results were fairly similar to what we hypothesized. As I mentioned, the primary end points of the trial has already been reported. Long-term data was consistent with what has previously been reported, and the timing and frequency of the BCL-2 mutations were pretty similar to what's been described in other cohorts of venetoclax-treated patients.

How do you expect these findings to impact the treatment of these patients in the future?

For patients where we see BTK mutations disappear even at the time of progression on venetoclax, [these findings are] provocative and suggest that we may be able to retreat some patients with a covalent BTK inhibitor after a BCL-2 inhibitor, even if they have previously been resistant to a BTK inhibitor. That’s an important result and will need to be confirmed with larger numbers of patients. The BCL-2 mutations are important because they show us a mechanism of resistance and tell us that we do need to further study those patients where we don't detect BCL-2 mutations at progression.

Reference

Woyach J, Popovic R, Rossi E, et al. Recurrent genomic alterations in the apoptotic machinery in patients with CLL treated with venetoclax monotherapy following treatment with BCRi. Presented at: 2023 iwCLL Annual Meeting; October 6-9, 2023; Boston, MA. Abstract 1553189.