Statins Enhance Venetoclax Response in CLL and MM

Statins, which are used to lower cholesterol, have shown a potential to induce apoptosis in various cancer cell lines, and evidence suggests a synergism when combined with BCL-2 inhibition. Based on this, researchers conducted a post-hoc analysis to see whether statins enhance the activity of venetoclax in patients with CLL or multiple myeloma (MM). Andrew W. Roberts, MS, at AbbVie Inc., in North Chicago, IL, discussed the findings at the ASH Annual Meeting.

The researchers collected data on patients with relapsed or refractory CLL from three single-arm, open-label, phase I or II trials of venetoclax monotherapy:

• Study 1 (NCT01889186) included patients with del(17p) mutation.
• Study 2 (NCT01328626) was a first-in-human, dose-escalation study in those with CLL or small lymphocytic lymphoma and non-Hodgkin lymphoma.
• Study 3 (NCT02141282) enrolled previously treated patients with CLL who had received ibrutinib or idelalisib.

They pooled data on patients with relapsed or refractory MM from two single‑arm, open-label phase I studies:

• Study 4 (NCT01794507) evaluated venetoclax in combination with bortezomib and dexamethasone (VenVd).
• Study 5 (NCT01794520) evaluated treatment with venetoclax monotherapy or venetoclax plus dexamethasone (VenDex).

Researchers previously reported that single-agent venetoclax activity is almost entirely restricted to patients with MM with the t(11;14) mutation, so analyses of response to venetoclax monotherapy or VenDex were limited to that subgroup.

In the CLL studies, 22% of patients received a statin, and those patients were more often male (79% versus 67%), aged 65 years or older (73% versus 54%), and enrolled at U.S. sites (69% versus 46%).

The proportion of any response (defined as overall response rate [ORR]) was similar in those with CLL who did or did not receive a statin (76.0% versus 74.9%); however, more statin users achieved complete remission ([CR], 26.7%) compared to those who did not (15.2%; p < 0.05). The unadjusted odds ratio (OR) for CR was 2.03 in favor of statin users (95% CI = 1.099–3.741; p = 0.03), and the corresponding multivariable-adjusted ORR was 2.676 (95% CI = 1.338–5.351; p < 0.01).

Progression-free survival and overall survival rates were consistent with CR rates, with multivariable-adjusted hazard ratios of 0.61 (95% CI = 0.383–0.956; p = 0.03) and 0.50 (95% CI = 0.247–1.007; p = 0.05), respectively.

A pharmacokinetic analysis showed no difference in venetoclax exposures between patients taking a statin and those who were not.

The trend for improved response among statin-treated patients was also present for the broad MM population treated with VenVd and among t(11;14)–positive patients with MM who were treated with venetoclax monotherapy or VenDex in Study 5. The ORR (including partial response or very good partial response or better) in Study 4 was 86.6% (n = 13/15) among statin users and 60.7% (n = 31/51) in those who did not receive statins. In Study 4, the ORR was 85.7% (n = 6/7) and 47.7% (n = 20/42), respectively (see Table 1 for more outcomes).

The researchers reported no unexpected safety observations in either disease cohort.

“Statins were associated with enhanced response to venetoclax in retrospective analyses of CLL and MM clinical trials,” the researchers concluded.

The post-hoc nature of the study design and lack of randomization are a limitation, and prospective, randomized trials are needed to confirm these findings.

Table 1. Response in Multiple Myeloma Studies

	Study 4		Study 5
Overall Response Rate	Statin	No Statin	Statin	No Statin
Very good partial response or better	53.3%	43.1%	57.1%	28.6%
Partial response	33.3%	17.6%	28.6%	19.1%