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Purpose: This global phase I trial investigated the safety, efficacy, pharmacokinetics, and pharmacodynamics of lisaftoclax (APG-2575), a novel, orally active, potent selective B-cell lymphoma 2 (BCL-2) inhibitor, in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (R/R CLL/SLL) and other hematologic malignancies (HMs). Patients and Methods: Maximum tolerated dose (MTD) and recommended phase II dose were evaluated. Outcome measures were safety and tolerability (primary) and pharmacokinetic variables and antitumor effects (secondary). Pharmacodynamics in patient tumor cells were explored. Results: Among 52 patients receiving lisaftoclax, MTD was not reached. Treatment-emergent adverse events (TEAEs) included diarrhea (48.1%), fatigue (34.6%), nausea (30.8%), anemia and thrombocytopenia (28.8% each), neutropenia (26.9%), constipation (25.0%), vomiting (23.1%), headache (21.2%), peripheral edema and hypokalemia (17.3% each), and arthralgia (15.4%). Grade ≥ 3 hematologic TEAEs included neutropenia (21.2%), thrombocytopenia (13.5%), and anemia (9.6%), none resulting in treatment discontinuation. Clinical pharmacokinetic and pharmacodynamic results demonstrated that lisaftoclax had a limited plasma residence and systemic exposure and elicited rapid clearance of malignant cells. With a median treatment of 15 (range, 6–43) cycles, 14 of 22 efficacy-evaluable patients with R/R CLL/SLL experienced partial responses, for an objective response rate of 63.6% and median time to response of 2 (range, 2–8) cycles. Conclusions: Lisaftoclax was well tolerated, with no evidence of tumor lysis syndrome. Dose-limiting toxicity was not reached at the highest dose level. Lisaftoclax has a unique pharmacokinetic profile compatible with a potentially more convenient daily (vs. weekly) dose ramp-up schedule and induced rapid clinical responses in patients with CLL/SLL, warranting continued clinical investigation.

GISTs are common malignant mesenchymal tumors that occur in the GI tract, with an estimated incidence rate of 1% to 2%. About 75% to 80% of patients with GIST have mutations in the KIT gene, while 5% to 10% have mutations in the platelet-derived growth factor receptor α (PDGFRA) gene. Tyrosine kinase inhibitors (TKIs) offer patients an improved quality of life but increased pharmacological resistance to TKIs is often observed. BCL-2 is expressed in >80% of GISTs, and amplification of BCL-2 and BCL-xL are common features associated with disease progression. One approach to enhance GIST eradication is to concurrently inhibit oncogenic KIT signaling while actively engaging apoptotic pathways. Olverembatinib (HQP1351) is a new, third-generation TKI that targets BCR-ABL1, KIT and PDGFRA and is currently in development for relapsed or refractory chronic myeloid leukemia and GIST. Lisaftoclax (APG-2575) is a selective BCL-2 inhibitor under development for hematologic malignancies. The purpose of this study was to evaluate whether combining a BCL-2 inhibitor, lisaftoclax, with olverembatinib enhances treatment effect on imatinib-resistant GISTs. Compared to imatinib-sensitive GIST cell lines (GIST882 and GIST-T1), increased BCL-2 protein expression was observed in imatinib-resistant GIST cells, particularly in GIST430, GIST48, and GIST48B lines. Cell-based antiproliferation studies showed additive activity of olverembatinib and lisaftoclax in imatinib-resistant GIST cells. In vivo studies using imatinib-resistant GIST430 cell-derived xenograft models further revealed that coadministration of olverembatinib at 15 mg/kg (every other day for 3 weeks) with lisaftoclax at 50 mg/kg (daily for 3 weeks) resulted in enhanced antitumor effects compared to either agent alone. Tumor growth inhibition (TGI) rates for combined treatment with olverembatinib and lisaftoclax reached 76.8%, which was superior to the TGI rate of either agent alone: 57.6% and 31.2% for olverembatinib and lisaftoclax, respectively. Regarding putative mechanisms, olverembatinib treatment was shown to downregulate BCL-xL and MCL-1 protein expression, possibly via inhibition of KIT signal pathway and downstream signal transducer and activator of transcription 3 (STAT3). Lisaftoclax triggered apoptosis by disrupting the BCL-2:BIM complex. Therefore, selective inhibition of BCL-2, aided by TKI-mediated MCL-1 and BCL-XL inhibition, markedly augmented cleavage of caspase-3 and poly (ADP-ribose) polymerase 1 (PARP-1), thus triggering apoptosis and subsequently enhancing antitumor effects. Our results demonstrate that olverembatinib and BCL-2 inhibitor lisaftoclax have additive antitumor effects in imatinib-resistant GIST. This novel dual approach may have the potential for treating patients with GISTs whose disease has progressed after treatment with TKIs. Citation Format: Ping Min, Guangfeng Wang, Eric Liang, Bingxing Wu, Huidan Yu, Dajun Yang, Yifan Zhai. Combination of olverembatinib (HQP1351) with BCL-2 inhibitor lisaftoclax (APG-2575) overcomes resistance in gastrointestinal stromal tumors (GISTs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1631.

In solid tumors, resistance to checkpoint inhibitors (CPIs) is frequently observed, partially due to upregulation of vascular endothelial growth factor A (VEGFA) and programmed death-ligand 1 (PD-L1). This culminates in an immunosuppressive tumor microenvironment and immune escape. Inhibitors against VEGF and the VEGF receptor (VEGFR) foster tumor vessel normalization and immunostimulatory reprogramming, in turn promoting treatment effects of immunotherapies. In recent years, TKIs, including axitinib, lenvatinib, and cabozantinib, plus immunotherapy have been approved to treat advanced RCC. Currently under clinical development for relapsed or refractory chronic myeloid leukemia and gastrointestinal tumor, olverembatinib (HQP1351) is a new-generation multikinase inhibitor with targets including VEGFR, fibroblast growth factor receptor (FGFR), SRC, BCR-ABL1, c-KIT, and platelet-derived growth factor receptor. The aim of this study was to assess whether olverembatinib combined with immunotherapy can promote inhibitory effects on RCC. In cell-free kinase assays, olverembatinib inhibited VEGFR1, -2, and -3 with IC50 values of 4.2, 6.1, and 4.1 nM, respectively. Compared to lenvatinib, olverembatinib had more potent antiproliferative effects on human umbilical vein endothelial cells. Olverembatinib also had antiproliferative activity in murine RCC lines RANCA and RAG, with IC50 values of 141 and 53 nM, respectively. When olverembatinib was coadministered with an anti-PD-1 antibody in a RANCA-derived syngeneic model, both agents exerted synergistic effects, with tumor growth inhibition rates reaching 60.6%. Mechanistically, olverembatinib influenced cancer cell proliferation directly by inhibiting phosphorylation of FGFR and downstream proteins. Increased cleavage of caspase-3 and poly (ADP-ribose) polymerase 1 were observed, suggesting induction of apoptosis. Olverembatinib also influenced proliferation of vascular endothelial cells by inhibiting phosphorylation of VEGFR, SRC, and downstream proteins Akt and extracellular signal-regulated kinases. Olverembatinib also reduced expression of PD-L1 in RCC cells. In tumor-infiltrating lymphocyte assays, olverembatinib increased numbers of cytotoxic T cells (CTL, CD8+) and natural-killer cells (NK, CD3−/CD49B+) in RANCA tumor tissues. Combined with an anti-PD-1 antibody, olverembatinib increased CTLs, NK cells, dendritic cells (DCs, MHC-II+/CD11C+), and M1 macrophages (F4/80+/CD11B+/CD86+) in RANCA tumor tissues, indicating an immunoregulatory effect of olverembatinib. Taken together, these data suggest that combining olverembatinib with a CPI confers synergistic antitumor effects in an RCC cancer mouse model by targeting tumor growth, angiogenesis, and immune regulation. This novel combination may provide an alternative approach to enhance treatment effects with CPIs in renal cancers. Citation Format: Guangfeng Wang, Eric Liang, Ping Min, Huidan Yu, Bingxing Wu, Dajun Yang, Yifan Zhai. Olverembatinib (HQP1351) enhances antitumor effects of immunotherapy in renal cell carcinoma (RCC). [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5071.

Natural killer/T-cell lymphoma (NK/TCL) is one of the most common subtypes (10.4%) of peripheral T-cell lymphoma, which in turn accounts for 10% to 15% of all cases of non-Hodgkin lymphoma. NK/TCL occurs more frequently in Asia and Latin America than other regions, and although associated with Epstein-Barr virus (EBV) infection, NK/TCL has an unclear pathogenesis of genetic and molecular alterations. Asparaginase-based chemotherapy regimens are frequently used, typically with unsatisfactory outcomes. Novel targeted therapies, such as histone deacetylase (HDAC) inhibitors and programmed death-1 antibodies, are reported effective either as single agents or in combination with other agents. Studies have also shown that EBV-positive NK/TCL cell lines are B-cell lymphoma-extra large (BCL-xL) dependent. Other preclinical experiments have shown that BH3-mimetic drugs targeting BCL-xL-induced cell death in NK/TCL cell lines were effective in NK/TCL xenograft models. BCL-xL inhibitors have shown narrow therapeutic windows in clinical trials because of dose-limiting on-target thrombocytopenia. Pelcitoclax (APG-1252) is a novel dual BCL-2/BCL-xL inhibitor under clinical development for solid tumors. As a result of its unique prodrug design, APG-1252 can overcome the undesired platelet toxicity. This study evaluated the potential antitumor effect of APT-1252 in preclinical models of NK/TCL. Cell-based antiproliferation studies showed activity of APG-1252 and its more potent metabolite APG-1252-M1 toward NK/TCL cell lines that overexpressed BCL-xL. Half-maximal inhibitory concentrations (IC 50) for APG-1252 in SNK-1, SNK-6, and SNK-8 (EBV-positive NK/TCL) cell lines were 2.652 ± 2.606 µM, 1.568 ± 1.109 µM, and 0.557 ± 0.383 µM, respectively. Corresponding values for APG-1252-M1 were 0.133 ± 0.056 µM, 0.064 ± 0.014 µM, and 0.020 ± 0.008 µM, respectively. Mechanistic studies demonstrated that APG-1252 and APG-1252-M1 disrupted the complex of BCL-xL/BCL-2-associated X protein (Bax) and BCL-xL/BCL-2 homologous antagonist killer protein (Bak) in SNK-6 cells, thereby liberating these proapoptotic proteins and further activating downstream apoptosis pathways by cleaving poly-ADP ribose polymerase-1 (PARP-1) and caspase-3. In an SNK-6 xenograft model, administration of APG-1252 at 65 mg/kg and 100 mg/kg either twice or once weekly resulted in significant antitumor effects, with tumor growth rate (T/C%) values ranging from 13.7% to 30.7%. Furthermore, the combination of APG-1252 with HDAC inhibitor chidamide or DDGP (dexamethasone, cisplatin, gemcitabine, and pegaspargase) chemotherapy demonstrated synergistic effects. Pharmacokinetic assessment in mice showed that APG-1252 had a long half-life in plasma (127 hours) and tumor tissues (25.2 hours), justifying intermittent dosing schedules used in vivo. Importantly, the transformation of APG-1252 to APG-1252-M1 was 16 times higher in tumor tissues compared to plasma (22% vs. 1.3%) after administration of APG-1252, thereby suggesting that APG-1252 can reduce platelet toxicity caused by APG-1252-M1 in plasma. In conclusion, APG-1252 has promising antitumor effects in NK/TCL, either as a single agent or in combination with an HDAC inhibitor or chemotherapy. These findings provide evidence to further evaluate APG-1252 as a potential treatment for NK/TCL. Disclosures Wang: Ascentage Pharma Co., Ltd., Shanghai: Current Employment, Current equity holder in publicly-traded company. Liang: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Ming: Ascentage Pharma Co., Ltd., Shanghai: Current Employment, Current equity holder in publicly-traded company. Rui: Ascentage Pharma Co., Ltd., Taizhou: Current Employment, Current equity holder in publicly-traded company. Tang: Ascentage Pharma Co., Ltd., Taizhou: Current Employment, Current equity holder in publicly-traded company. LV: Ascentage Pharma Co., Ltd., Shanghai: Current Employment, Current equity holder in publicly-traded company. Ge: Ascentage Pharma Co., Ltd., Shanghai: Current Employment, Current equity holder in publicly-traded company. Zhang: Ascentage Pharma Co., Ltd., Taizhou: Current Employment, Current equity holder in publicly-traded company. Wang: Ascentage Pharma Co., Ltd., Taizhou: Current Employment, Current equity holder in publicly-traded company. Shang: Ascentage Pharma Co., Ltd., Shanghai: Current Employment, Current equity holder in publicly-traded company. Yang: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding. Zhai: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding; Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding.

Treatment with tyrosine kinase inhibitors (TKIs) directed against the ATP-binding site of BCR-ABL promotes recovery of Ph+ leukemia. However, emergence of gatekeeper mutation T315I and compound mutants confer resistance to these TKIs. The allosteric inhibitor, asciminib, effectively inhibits BCR-ABL kinase through binding to the myristoyl-binding site. Combining asciminib with ponatinib can overcome only a subset of the resistance caused by BCR-ABL compound mutants. Olverembatinib (HQP1351) is a new generation TKI targeting BCR-ABL and currently in development for r/r CML. The purpose of this study is to evaluate whether a novel combination of olverembatinib and asciminib, targeting both ATP pocket and allosteric region of BCR-ABL protein, can promote the inhibitory effect on the kinase harboring compound mutations. A series of cell lines expressing BCR-ABL single or compound mutations were constructed based on BaF3 murine pro-B cell line. Effect of olverembatinib as a single agent or in combination with asciminib were analyzed using antiproliferation assay, Western blot and FACS assays in vitro. In vivo efficacy was evaluated using the syngeneic mouse model derived from BaF3 cells with T315I or compound mutations. The cell based antiproliferation studies demonstrated superior activity of olverembatinib toward BCR-ABL single or compound mutations with IC50 values ranging between 6-300 nM. In particular, olverembatinib was more effective than ponatinib, asciminib and other TKIs against those compound mutations. Moreover, the combination of olverembatinib with asciminib was highly effective against BCR-ABL compound mutations, especially those containing T315I. In vivo studies further revealed that co-administration of olverembatinib with asciminib resulted in significant prolongation of survival compared to single agents. Importantly, the anti-tumor effect was more potent than that of ponatinib plus asciminib in models harboring compound mutations. In terms of mechanism, the combined treatment synergistically downregulated phosphorylation of BCR-ABL and the downstream proteins CRKL and STAT5, and augmented cleavage of Caspase-3 and PARP-1, thus triggered apoptosis and subsequently enhanced the antitumor effects. Our results demonstrated that the combination of ATP binding site inhibitor olverembatinib and allosteric inhibitor have synergistic anti-tumor effect on tumor cells harboring single or compound mutations in BCR-ABL. This novel strategy may help to overcome the secondary compound mutations post the treatment with TKIs. Citation Format: Guangfeng Wang, Jing Lv, Chunyang Tang, Ping Min, Li Rui, Fei Zhang, Lvcheng Wang, Yangfeng Ge, Kejie Lian, Eric Liang, Dajun Yang, Yifan Zhai. ATP-site inhibitor olverembatinib, HQP1351, enhanced the effect of allosteric inhibitor on the resistance conferred by the compound mutations of BCR-ABL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1463.

Keywords: MDM2; Immuno-oncology; PD-1 Background APG-115 is an orally active small-molecule MDM2 inhibitor that potently binds MDM2 protein, restores TP53 function, and activates p53 - mediated apoptosis in tumor cells retaining wild-type p53. Preclinical studies demonstrated that APG-115 promoted the production of proinflammatory cytokines in T cells, enhanced CD4+ T cell activation, and increased PD-L1 expression on tumor cells. Enhanced antitumor activity was demonstrated in syngeneic tumor models after APG-115 combined with PD-1 blockade. Retrospective clinical analyses suggested that MDM2 amplification is associated with hyper-progression in the patients treated with check point inhibitors. Keywords: MDM2; Immuno-oncology; PD-1 In general, by targeting MDM2-p53 pathway, APG-115 in combination with PD-1/PD-L1 blockade may provide a novel strategy to reverse immunosuppression and/or enhance antitumor immunity in the cancer patients who were either failed to standard therapies or resistant to IO therapies. Methods This dose escalation study (NCT03611868) combines APG-115 with pembrolizumab for the treatment of patients with metastatic solid tumors. Four dose levels of APG-115 have been tested: 50, 100, 150, and 200mg. APG-115 is administrated orally every other day (QOD) for consecutive 2 weeks of a 21-day-cycle with pembrolizumab at 200mg IV on day1 of a 21-day-cycle. Results Through June 15, 2019, a total of 14 patients have been treated in 4 cohorts of APG-115 in combination with pembrolizumab IV q3weeks. No cycle 1 DLTs have been observed up to and including 200 mg APG-115 at total doses of APG115 that are equivalent to the single agent MTD of APG-115 alone. Eleven patients experienced at least 1 TEAE. The most common TRAEs (≥10%) were nausea (42.9%), neutrophil count decreased (21.4%), vomiting (14.3%), decreased appetite (14.3%), diarrhea (14.3%), platelet count decreased (14.3%), white blood cell count decreased (14.3%), and fatigue (14.3%). Four patients experienced at least 1 grade 3 or higher TRAE beyond course 1 including neutrophil count decreased (21.4%). Five SAEs occurred in 3 patients, but only one grade 3 febrile neutropenia was treatment related. One patient with advanced ovarian cancer with a germline ATM mutation, refractory to 6 prior lines of therapy, has a sustained “confirmed CR” that continues beyond 12 cycles at the 100mg cohort. A patient with advanced NSCLC in 100mg cohort has received “confirmed PR” (still ongoing) after failed prior 5 lines of therapies including 3 months’ nivolumab treatment; 5 patients had SD after two cycle treatments, 2 of them ongoing. PK analyses indicates an approximately dose proportional increase in exposure across dose levels from 50 to 100 mg with plasma concentrations that exceed those that portend MDM2 inhibition. Preliminary pharmacodynamic (PD) results showed that the serum macrophage inhibitory cytokine-1 (MIC-1) levels are elevated in the APG-115 treated patients, suggesting a potential p53 activation in patients. Conclusion APG-115 in combination with pembrolizumab is well tolerated. The MTD has not been exceeded at full doses of APG-115. Promising anti-tumor effects have been seen in several tumor types when in combination with pembrolizumab. Expansion cohorts in molecularly selected patients is planned. Citation Format: Anthony W Tolcher, Raghad Karim, Yuefen Tang, Jiao Ji, Hengbang Wang, Lichuang Meng, Angela Kaiser, Jennifer Coe, Eric Liang, Christina Rosas, Dajun Yang, Yifan Zhai. Phase Ib study of a novel MDM2 inhibitor APG-115, in combination with pembrolizumab in patients with metastatic solid tumors in U.S. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A086. doi:10.1158/1535-7163.TARG-19-A086