Abstract SY24-02: Remarkable early clinical activity with the Bcl-2 selective inhibitor ABT-199: Proving the concept.
Authors: Rod Humerickhouse
Journal: Cancer Research (2013)

Abstract Altering the dynamic binding interactions between pro-death (e.g., BAX, BAK, BAD, BIM, NOXA, PUMA) and pro-survival (BCL-2, BCL-XL, BCL-W, MCL-1, BFL-1) BCL-2 family proteins is one means by which cancer cells undermine normal apoptosis and gain a survival advantage. BCL-2 plays a dominant role in the survival of lymphoid malignancies where BCL-2 over-expression is mediated through multiple mechanisms, including amplification, gene translocation (t14:18) and loss of suppressive microRNAs (miR15a and MiR16-1). BCL-XL, a related pro-survival protein, is associated with drug resistance and disease progression of solid tumors and some hematological malignancies. BCL-2 family proteins also regulate survival in non-tumor tissues; e.g. BCL-XL is the primary survival factor in platelets. The association of pro-survival BCL-2 protein family members with tumor initiation, disease progression, and drug resistance makes them compelling targets for antitumor therapy. Although direct antagonism of protein-protein interactions is a longstanding challenge in drug discovery, two orally bioavailable small molecule BCL-2 family inhibitors, navitoclax and ABT-199, are in clinical development. Navitoclax, the 1st-generation molecule, has high affinity for both BCL-2 (Ki=.04 nM) and BCL-XL (Ki=.05 nM). Navitoclax alone induces rapid apoptosis of CLL cells ex vivo and complete tumor regressions in xenograft models of acute lymphoblastic leukemia and small-cell lung cancer. In other xenograft models where single agent activity is not observed, which includes models of aggressive B-cell lymphoma, multiple myeloma and numerous solid tumor malignancies, navitoclax significantly enhances the efficacy of a broad spectrum of clinically relevant therapeutic regimens. The mechanisms associated with this potentiation include down-regulation or inhibition of MCL-1 and upregulation of BIM. Our data and those published by others demonstrate that sensitivity to small molecule BH3 mimetics is not typically determined by overexpression of antiapoptotic proteins such as BCL-2 alone, but rather is dependent upon the overall balance of anti- and pro-apoptotic BCL-2 family members present. In the clinic, inhibition of BCL-XL by navitoclax induces a rapid, concentration-dependent decrease in circulating platelets, as predicted by preclinical data. This mechanism-based thrombocytopenia is the dose-limiting toxicity of single-agent navitoclax in patients and limited the ability to achieve drug concentrations necessary to fully explore the potential of BCL-2 inhibition. Nevertheless, early signs of clinical antitumor activity were observed in lymphoid malignancies thought to be dependent on BCL-2 for survival. A response rate of 33% was observed in patients with relapsed or refractory CLL. In a randomized Phase 2 trial in previously untreated patients with CLL the combination of navitoclax with rituximab demonstrated an increase in overall response rate when compared to rituximab alone (response rate 55% with 12-week treatment or 70% with continued treatment, compared with 35% for rituximab alone). In Phase 1 combination studies with cytotoxic chemotherapies such as taxanes, platinum agents, etoposide and irinotecan, as well as erlotinib, navitoclax exacerbated dose-limiting toxicities such as neutropenia and diarrhea associated with the combining agents, limiting the opportunity to reproduce preclinical studies demonstrating combination efficacy in solid tumor models. In response to the observed dose-limiting thrombocytopenia with navitoclax and the activity observed in B-cell malignancies, ABT-199, a first-in-class BCL-2 selective inhibitor was achieved using structure-guided rational design. ABT-199 binds with subnanomolar affinity to BCL-2 (Ki&amp;lt;0.010 nM), but has up to 4000-fold less affinity for BCL-xL (Ki=48 nM). ABT-199 demonstrates antitumor activity in a variety of BCL-2-dependent human cell lines and tumor xenograft models that include B cell NHL, follicular lymphomas (FL), diffuse large B-cell Lymphoma (DLBCL) and mantle cell lymphoma (MCL), in addition to subsets of acute and chronic leukemia. These tumor cells that are sensitive to single agent ABT-199 treatment are characterized by high BCL2 expression, and often show high BCL-2:BIM complexes and low MCL-1 expression as well. In contrast to its higher potency against BCL-2 dependent tumor cells, ABT-199 is substantially less potent against platelets ex vivo and in vivo as compared to navitoclax. In the initial phase-I dose-escalation trial in patients with either relapsed/refractory CLL or NHL, ABT-199 is demonstrating substantially greater activity than that seen with navitoclax as well as dramatically reduced effects on platelet counts. These early results are consistent with the hypothesis that a BCL-2 selective (BCL-XL-sparing) inhibitor would reduce the incidence of thrombocytopenia and provide an increased therapeutic index for patients. In CLL, a cancer type that has been described as “primed for death” due to over-expression of BCL-2 and abundance of BCL-2:BIM complexes, reductions in circulating lymphocyte counts and apoptosis of CLL cells are being observed within hours of ABT-199 dosing. Tumor lysis syndrome is dose-limiting for ABT-199 in patients with CLL, particularly at first exposure. Management of tumor lysis syndrome in CLL has required reduction of the ABT-199 starting dose and modification of the dosing regimen to include a 2 to 3 week lead-in period with step-wise increases to the final dose. Small molecule BCL-2 inhibitors are active as single agents in cancer types dependent upon BCL-2 for survival. The BCL-2 selective compound ABT-199 shows particular promise in CLL as a single agent and may have a role as a single agent in other B-cell malignancies. For other diseases in which BCL-2 is over-expressed, and for solid tumors where BCL-XL is the relevant target, combination therapy is likely to be required. The full potential of BH3 mimetic therapy requires additional translational research to identify tumor profiles predicting sensitivity and to identify tolerable combinations that induce a sensitive profile. Citation Format: Rod Humerickhouse. Remarkable early clinical activity with the Bcl-2 selective inhibitor ABT-199: Proving the concept. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY24-02. doi:10.1158/1538-7445.AM2013-SY24-02