Introduction
The B cell lymphoma 2 protein (BCL-2) family proteins comprise the sentinel network that regulates the mitochondrial or intrinsic apoptotic response [
1]. A recognized hallmark of cancer development, overexpression of anti-apoptotic BCL-2 family proteins mediates resistance to chemotherapy in experimental models of lymphoma, and is associated with poorer prognosis in patients with diffuse large B cell lymphoma (DLBCL) treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) [
4]. Venetoclax, a selective inhibitor of BCL-2 [
5], is approved globally for monotherapy or combination therapy in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), as well as treatment-naïve unfit patients with acute myeloid leukemia [
6,
7]. Venetoclax has also demonstrated significant clinical activity across a broad range of non-Hodgkin lymphoma (NHL) subtypes [
8].
CAVALLI is a phase 1b/2 multicenter, open-label study investigating the safety and efficacy of venetoclax plus an anti-CD20 antibody (rituximab [R] or obinutuzumab [GA101; G]) in combination with standard CHOP chemotherapy in patients with NHL. The phase 1b portion of the study included two parallel treatment arms, with planned venetoclax doses ranging from 200 to 800 mg orally at two different dosing schedules: once daily (21 days per cycle) or a noncontinuous dosing schedule of 10 doses in a 21-day cycle (10/21-day dosing), plus standard cycles of R-CHOP or G-CHOP in relapsed/refractory (R/R) or previously untreated patients with NHL [
9]. A greater than anticipated incidence of hematologic toxicity was evidenced by dose-limiting toxicities (DLTs) at the initial starting dose of 200 mg administered daily in a 21-day cycle for eight cycles. The phase 1b part of CAVALLI established the recommended phase 2 dose of venetoclax as 800 mg in a 10/21-day dosing schedule, i.e., days 4–10 of cycle 1 and days 1–10 of cycles 2–8, in combination with R for eight cycles and CHOP [
9] for 6–8 cycles in patients with first-line (1L) DLBCL. The incidence of hematologic toxicity observed in patients following this schedule was lower than in patients following the once-daily dosing schedule; as such, the noncontinuous dosing schedule was preferred, given that it allowed administration of higher doses of venetoclax. The G-CHOP arm was not expanded to phase 2 in the light of results from the phase 3 GOYA study in 1418 patients with previously untreated DLBCL, which showed no improvement in progression-free survival (PFS) with G-CHOP over R-CHOP in 1L therapy [
9,
10].
After 30.8 months’ median follow-up, venetoclax plus R-CHOP continued to be associated with improved investigator-assessed (INV)-PFS in the all-comer 1L DLBCL population (adjusted Cox regression hazard ratio of 0.61; 95% confidence interval [CI] of 0.43–0.87), compared with matched controls from the GOYA study. Promising efficacy (PFS) was evident in the poor prognostic BCL-2-immunohistochemistry (IHC)-positive subpopulation (adjusted Cox proportional hazards [CPH] ratio of 0.55; 95% CI of 0.34–0.89 in CAVALLI versus the R-CHOP arm of GOYA) [
11].
As a complementary report to the initial efficacy, safety, and biomarker analyses of CAVALLI phase 2 [
11], the present study investigated population pharmacokinetics (PopPK) and exposure–response (ER) characteristics of venetoclax from CAVALLI to confirm the dose selection of venetoclax in combination with R-CHOP chemoimmunotherapy for future studies.
Discussion
In the CAVALLI study, evidence of the positive benefit–risk profile for venetoclax administered at a dose of 800 mg in a 10/21-day cycle was demonstrated, particularly for BCL-2-IHC-positive patients with 1L DLBCL, when compared with historical data from the R-CHOP arm of the GOYA study [
10].
The PK of venetoclax in CAVALLI were adequately described using a previously developed legacy PopPK model. However, upon evaluation of the legacy model (when applied to the CAVALLI data) using diagnostic plots, lower exposures for the patients enrolled in CAVALLI were noticeable compared with the patients with R/R NHL previously evaluated in the legacy model at similar dose levels. It is known that increased fat intake increases venetoclax exposure [
18] and therefore it could be speculated that the lower exposures in the CAVALLI study may be attributed to the lower fat content in the meal-type, i.e., 23% and 3.5% of fat calories in the meal as recommended in the CAVALLI protocol, compared with the 30% of fat calories following the completion of the standard low-fat breakfast for the patients with R/R NHL included in the legacy PopPK model. Moreover, we were not able to consider these differences in fat content of 23% and 3.5% in the PopPK model as both meals were classified as low-fat meal type in the CAVALLI study. Subsequently, a study (CAVALLI) effect of 1.63 on CL/F and 2.33 on V2/F (values higher than those reported for the historical studies) was added in the updated PopPK model to account for the possible differences between the population of CAVALLI study patients relative to the population of patients from the prior analysis.
Furthermore, in contrast to the legacy model, the present PopPK model did not include the co-administration of R as a covariate on CL/F of venetoclax. In the legacy model, concomitant R administration was estimated to increase the venetoclax CL/F by 1.21-fold based on a small sample size of 50 subjects receiving venetoclax + R [
13]. However, subsequent analysis in a much larger patient population (the phase 3 MURANO study, where 181 patients with R/R CLL were randomized to receive venetoclax plus R) showed a minimal 7% increase in the CL/F for venetoclax when co-administered with R, supporting removal of the R/G covariate from the model [
19]. The legacy model and phase 3 MURANO study suggest that neither R, which leads to a rapid depletion of CD20
+ B cells, nor indication type (whether CLL, SLL, or NHL; all of which are characterized by varying levels of circulating B cell lymphocytes) has any apparent impact on venetoclax PK [
13,
19]. Taken together, this indicates minimal impact of B cell subtypes on venetoclax PK (although this was not specifically tested as a covariate in the PopPK model).
Previous studies have evaluated the venetoclax ER relationships in subjects with CLL, NHL, or multiple myeloma [
20‐
24]. ER analyses were performed to confirm the dose selection of venetoclax in combination with R-CHOP chemotherapy for future studies. PopPK-predicted AUC
ss nominal was used as an exposure metric for predicting clinical response, i.e., efficacy, safety, or tolerability of venetoclax. We used AUC
ss nominal as the exposure metric for the ER analysis rather than average plasma concentration to the time of the event (
Caverage) to avoid bias due to a correlation between lower exposures from dose reductions and response, both of which are more likely the longer a patient is on study. Moreover, AUC
ss nominal isolated the impact of assigned target venetoclax dose and associated steady-state exposure on safety and efficacy, and was not subject to confounding by complex interactions between time and treatment-related or disease-related changes to venetoclax or R-CHOP dosing. To isolate the treatment effect of venetoclax, the ER analyses referenced clinical data from the R-CHOP arm of GOYA.
Promising efficacy for PFS and improved efficacy for PET-CR rate assessed at EOT in CAVALLI compared with matched GOYA controls were consistent with the venetoclax mechanism of action [
12]. However, the graphical and CPH analysis of the patients treated at the 800 mg dose in the phase 2 portion of the CAVALLI study showed no statistically significant relationship between venetoclax exposure and PFS in both all-comers or BCL-2-IHC-positive subpopulations, which suggests no evidence of additional efficacy with increasing venetoclax exposure in this trial. This is further confirmed by the logistic regression analyses using PET-CR rates, where increased venetoclax exposure did not translate into improved efficacy in both the all-comers or BCL-2-IHC-positive subpopulations at the 800 mg (10/21-day cycle) dose.
Although no statistically significant exposure-PFS or exposure-PET-CR trends were observed in these analyses, the results are not considered sufficiently strong enough to confidently predict efficacy at alternative venetoclax doses, as the majority of patients in the exposure-efficacy analyses were studied at a single venetoclax dose level of 800 mg and a wide CI was observed around exposure-efficacy predictions for the BCL-2-IHC-positive subpopulations.
Furthermore, compared with CLL, where the labeled venetoclax dose is 400 mg, a venetoclax dose resulting in a higher steady-state exposure in NHL may be required because of a potential decreased sensitivity to venetoclax of lymphocytes located in the lymph node compared with the blood as reflected in the lower half maximum effective concentration (EC50) values of venetoclax for circulating lymphocyte counts (0.00863 μg/mL) compared with tumor size (0.146 μg/mL) [
21]. This increased sensitivity of circulating CLL cells than CLL cells within a tumor mass may be attributed to the reduced blood flow and subsequent delivery of systemic venetoclax within a tumor, and due to survival signals cells receive when in direct contact with other cells within the tumor microenvironment. It is therefore not surprising that DLBCL sensitivity is lower compared with CLL, as the bulk of the disease is non-circulating (in lymph nodes and other tissues in the body).
As long as delivery of the potentially curative standard of care R-CHOP therapy is not compromised, the addition of venetoclax is considered to pose a low risk for negatively impacting outcome in patients with 1L DLBCL. In the current study, patients with higher venetoclax exposures showed similar dose intensities for the individual components of venetoclax and R-CHOP combination therapy compared with patients with lower venetoclax exposures, suggesting that patients with higher initial venetoclax exposure did not have higher probability to maintain or reduce their venetoclax or R-CHOP backbone dose. This finding supports the proposal that addition of venetoclax to R-CHOP did not compromise delivery of R-CHOP therapy.
Logistic regression analysis of exposure-safety data from the patients in the CAVALLI study showed no statistically significant associations between venetoclax exposure and the probability of clinical manifestations of toxicity (i.e., grade ≥ 3 febrile neutropenia, grade ≥ 3 infections, and/or SAEs), or grade ≥ 3 neutropenia or grade ≥ 3 thrombocytopenia. The prognostic impact of the tested covariates has been previously reported. [
25‐
28]
Although a higher incidence of AEs was generally seen for patients with 1L DLBCL in the CAVALLI study compared with the GOYA historical control (R-CHOP), the reported AEs were manageable and predictable on the basis of the mechanism of action of venetoclax, or consistent with the known safety profile of R-CHOP [
29,
30]. The interpretation of these events could be confounded by the additional mandatory mid-cycle laboratory tests and clinical evaluations required for the CAVALLI study but not required in the GOYA trial. Taken together, there was limited evidence to suggest that administering 800 mg of venetoclax would cause additional toxicity compared with the lower venetoclax doses administered to patients in the CAVALLI study; however, it is possible that higher doses could lead to increased safety events.
Acknowledgements
Venetoclax is being developed in collaboration between Genentech, Inc. and AbbVie Inc. The authors thank the patients who participated in the CAVALLI and GOYA studies and their families, as well as the study co-investigators, research nurses, and coordinators at each of the clinical sites. The authors also thank Sandhya Girish for her input into data analyses and manuscript development.